BASIC HUMAN EMBRYOLGY

EMBRYOLGY FIRST EDITION

S.M.DAWAR HUSAIN HUMAN EMBRYOLOGY

ByS. M. DAWAR HUSAINMS.(Aligarh)DEPARTMENT OF ANATOMYJ N Medical CollegeA M U Aligarh

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First Edition 2006

All rights reserved . No part of this publication may be reproduced or transmitted , in any formby any means without written permission fromthe author .

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PREFACE(First Edition)

This book on human embryology has been written with the effort to make it brief, to the point and time saving for the medical students. It is felt over the time that if all the facts regarding this subject are collected in a book in precise and to the point manner than it can serve the students in a better way.In this book heed has been paid to the aspect that the language should be kept as simple & clear as possible so that the average and even the below average student is ableto comprehend.

Care has also been taken in expressions to transfer the concepts in the minds of the students as clearly as possible with proper relevant illustrations.

It is hoped that this tiny weak seedling of work may grow into a big useful tree by addition of the suggestions which are expected from the distinguished anatomists.Medical students are expected to communicate any problem and suggestion they have in relevance to this book so that changes can be made accordingly to satisfy their need.

August 2006 S. M. Dawar Husain

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CONTENTS

1. Introduction

2. Gametogenesis

3. The Uterine (Menstrual) Cycle

4. Formation of Germ Layers & Embryonic Disc

5. Developmental Outcome of Embryonic Disc

6. Development of the Placenta

7. Development of the Human Body Tissues

8. The Skin & its Associated Structures

9. The Pharyngeal Arches & their Derivatives

10. Development of The Human Skeleton

11. Formation of Face & Palate

12. Development of the Alimentary canal & Associated Structures

13. Formation of Human Body Cavities & Respiratory System

14. Formation of Liver, Pancreas & Spleen

15. Development of the Cardiovascular System

16. Development of the Urogenital System

17. Development of the Nervous System

18. The Human Eye & Ear

19. Formation of Hypophysis Cerebri & Adrenal , Pineal Glands

20. Dervatives of Germ Layers & General Embryology

21. Basics of Genetics

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1Introduction

Embryology is the study of the formation and development of the fertilized product or zygote or fertilized ovum from the time of it’s fertilization uptill it’s birth as a newborn individual. This intra-uterine life period is about 9 months or 38 weeks or 266 days approximately. In the first 2 months of this intra-uterine life the developing individual is called an embryo and after 2months uptill birth the reproductory product is known as fetus.

In the first 2 months of intra-uterine life the developing human individual achieves a form that can be distinguished as human and the main organs become distinctly visible.

The understanding of adult human gross anatomy can be made on the basis of understanding of various human intra-uterine developmental processes in the human unborn reproductory product through the science of embryology as also the different developmental anomalies of the human body organs and other human body parts can be understood in a better manner by going through the human developmental process and appropriate treatment can be considered accordingly. Vice versa, the development of the human body parts can be analysed more clearly in the background of the knowledge of the human histology and gross human anatomy.

Any stage of deviation in the sequence of normal developmental process, which in turn leads to abnormal or maldevelopment of particular human body part or organ, can be spotted out by embryological study and the factors responsible for such deviations can be analysed. Subsequently, the factors responsible for such deviations can be pin-pointed and removed or appropriate treatment to curb the particular deviation or abnormality can be considered.

Zygote is the fertilized egg or fertilized ovum or fertilized product or reproductory product formed as result of fusion of male and female gametes. The male gamete is called spermatozoon (plural is spermatozoa) and the female gamete is called ovum (plural is ova). These gametes which are specialized to bring about reproduction are produced in the gonads. The gonads are the sex organs. Male sex organ or gonad is the testis ( plural is testes) and the female sex organ is the ovary ( plural is ovaries).These specalized gametes are few in number as compared to millions of other cells of the human body.

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The process of formation of the gametes in the gonads or sex organs is known as gametegenesis. The gametogenesis in the males concerns with the formation of spermatozoa in the testis and is called the spermatogenesis whereas in the females it deals with the formation of ova in the ovary and so called the oogenesis. The gametogenesis is the result of cell division and cell division involves the chromosomes.

Chromosomes are the condensed form of chromatin network in the nucleus of the cell formed in the process of cell division. The number of chromosomes in each cell.

2. Human Embryology

Differs from one species to the other. In human beings there are 46 chromosomes in each cell.This 46 number of chromosomes in the humans is called the diploid number.Each of the human gamete cells (spermatozoa and ova) has 23 number of chromosomes which is half of the human diploid number of chromosomes. This 23 number of chromosomes in the human gamete cell is known as the haploid number.

2 of these 46 chromosomes in each human cell are sex chromosomes and rest of the 44 chromosomes are referred to as autosomes.The sex chromosomes are of two types, X or Y.The human female has 44 autosomes and two X chromosomes in each cell . In comparison the human male has 44 autosomes ,one X and one Y chromosomes in each cell.Exactly identical or homologus chromosomes, in these 44 human autosomes, get paired to form 22 pairs of chromosomes ; while the sex chromosomes form the 23rd pair containing two X chromosomes in the human female cell where as one X and one Y chromosomes in the case of the human male cell. So from 46 chromosomes 23 pairs of chromosomes are formed. In each of these 23 pairs, one chromosome comes from the father side and the other from the mother side.

Each chromosome contains two parallel bars called chromatids knotted to each other, the knot area of contact between the two parallel chromatids is called the centromere or kinetochore. The centromere divides each chromatid length into a short arm on one side and a long arm on the other as illustrated in Fig 1b.

Each chromosome has total length, short arm length,long arm length and other characterstics which are specific to itself and which help in identifying it individually & demarcating it from the other chromosomes. So, chromosomes can be classified on the basis of these individual differences and this sort of classification of the chromosomes is known as karyotyping.

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Any anomaly in terms of the number of chromosomes or in terms of indiyidual character of the chromosomes can be identified with the help of karyotyping.

Chromosome and InheritenceInheritence of characters from parents to offsprings takes place through the structures called genes which are present in each chromosome. Genes in the chromosomes of the human fertilized ovum contain all the information necessary for the development and formation of the numerous tissues and organs of the entire human body and their proper placement within the human body and function throughout life. Genes are the units which control and guide the particular cellular functions for the development of particular features of a species or of an individual. Nowadays a lot of research work is going on regarding how the chromosomes and genes store and use the great volume of information.

The nucleic acid called deoxyribonucleic acid (DNA), is the main constituent of the chromosomes, in the molecules of which all information is stored. Each of the large number of genes is composed of specific DNA molecular sequence .This specific DNA molecular sequence which is specific to only one gene, helps in differentiating all the genes from each other. Particular genetic information, when required, leads to the

3. Human EmbryologySynthesis of particular proteins to direct particular activities of the

cell. So, nature and function of the cell is based on proteins synthesized by it. Each cell differs structurally and functionally from another cell due to differences in the proteins that are synthesized by it’s genes and those that constitute it. Characters of each individual and each species differ from the other due to differences in the combination of genes and accordingly in the combination of proteins present within the body. The genes by synthesizing particular proteins bring about the development of particular features of a species or an individual .

Cell DivisionNew cells multiply within the body by the division of pre-existing

cells. This multiplication of cells, further adds to the development of the embryo and after the birth is required for growth and for replacement of dead cells.

In the process of cell division and multiplication, transfer of the entire genetic information from the chromosomes of pre-existing mother cells to each of the daughter cells takes place . We know how much essential this transfer of genetic information is for the development and

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functioning of different cells and tissues; and finally , of the entire human body .

Cell division is called mitosis when the chromosomes of the resultant daughter cells are identical in number and genetic content to those of the mother cells and this sort of cell division occurs in the somatic cells of the body . Another form of cell division which takes place in the sex gland cells of the body is called meiosis where the resultant daughter cells are called gametes . Here in the resultant gametes, the number of chromosomes is reduced to half the normal number in the mother cell and also the genetic information in different gametes produced is not identical to each other as well as to the mother cell.

MitosisSomatic mother cells of the body, at the end of their life span, divide into two daughter cells . These daughter cells, after completing their functional period, serve as mothercells for the next division to give rise to next generation daughter cells and the process continues in this manner . The period during which active mitotic division process of the cell is going on is referred to as the phase of mitosis, whereas, the interval period between two successive divisions is known as interphase .

Based on the sequence of events occurring during the mitosis, each mitosis is divided conventionally into 4 stages. These stages are prophase, metaphase, telophase and anaphase.

Prophase is the stage during which mitosis begins. During this phase the gradual coiling of the chromatin of the chromosome gives the chromosome first thread-like form and subsequently a rod-like shape. These rod-like chromatids can be distinctly identified

4. Human EmbryologyTowards the end of the prophase. Two identical chromatids

constitute each chromosome and give chromosome it’s typical structure. Simultaneously, along with these changes of chromosomes, the two centrioles of the cell move apart to opposite poles of the cell.

While separating the centrioles produce microtubules which connect the two centrioles and form a spindle in between. Along with these changes, the nuclear membrane breaks down and nucleoli vanishes. This stage is followed by metaphase.

Metaphase is the stage in which the chromosomes position themselves at the equator of the cell midway between the two

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centrioles and each chromosome is attached to the microtubules of the spindle by it’s centromere .

Anaphase is the stage in which the centromere of each chromosome breaks longitudinally and the two separated chromatids become independent chromosome each. So at this stage of anaphase forty six pairs of chromosomes can be considered to be present in the dividing cell. Two chromosomes of each pair move along the spindle to opposite poles of the cell during this stage.

Telophase is the stage which follows anaphase. At this stage two daughter nuclei are formed with the appearance of nuclear membranes along with reappearance of nucleoli and the chromosomes become thin and inconspicuous by their gradual elongation .These changes are accompanied by the division of the cytoplasm as well as presumably duplication of the organelles .At the same time cell membrane of the dividing cell also undergoes a process of division untill the formation of almost two separate cell membranes of forming daughter cells .The centriole undergoes duplication at this stage or in early period of the subsequent interphase.

In the interphase, the two daughter cells get completely separated from each other. Preceding the next mitotic division, the DNA content of the chromosomes duplicates during the interphase as occurs during the interphase before the meiotic division.

MeiosisMeiosis takes place by two (first and second) successive meiotic

divisions. As against mitosis which takes place in somatic cells of the body, meiosis occurs in sex cells.

First Meiotic DivisionFirst meiotic division also contains the four stages as in mitosis,

i.e., prophase, metaphase, anaphase and telophase.Prophase: This stage is long with certain special and specific changes that it is conventionally divided into certain substages as follows:

5. Human Embryology

1. Leptotene: Though the chromosome can be seen in leptotene but it’s two chromatids can not be identified.2. Zygotene: Here the chromosomes of each pair come to lie in apposition to each other in a parallel fashion. This sort of pairing arrangement is called conjugation or synapsis . So the 46 chromosomes in each cell are paired in 23 pairs. In these 23 pairs of chromosomes, one is sex-pair containing XX chromosomes (female) or XY

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chromosomes (male). Bivalent is formed by the two chromosomes of a pair . 3. Pachytene: Each chromosomal pair (bivalent) is now termed as a tetrad due to the distinct appearance of four chromatids . Each chromosome of a pair has one central and one perepheral chromatid .The two central chromatids of each chromosomal pair inter-coil with each other and cross at multiple points. This crossing of the two chromatids is termed as crossing over. While crossing, the two chromatids become adherent and these points of adherence are known as chiasmata .4. Diplotene: Here, the chromatids break at the points of crossing over as the two chromosomes of a pair tend to move apart and the broken loose pieces get attached to the opposite chromatid. This is how genetic material is exchanged between these opposite chromatids.

Metaphase Meiotic metaphase is same as the metaphase in mitosis.

Anaphase Here , there is no splitting of the centromeres as against the anaphase in mitosis and the two entire chromosomes of a pair move apart from each other to the opposite pole of the spindle . This leads to each of the daughter cells containing 23 chromosomes and each of the chromosomes having two chromatids.

Telophase Meiotic telophase is similar to mitotic telophase.

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2Gametogenesis

SPERMATOGENESIS

Sypermatozoa are formed in the wall of the seminiferous tubules of the testes. If we look at one of these tubules under a microscope, we find that there are many cells of different sizes and shapes. Most of these represent stages in the formation of spermatoazoa, but some (called Sertoli cells) have only a supporting function.

The various cell-stages in spermatogenesis are as follows (the number of chromosomes at each stage is given in brackets):

(A) The spermatogonia (type A) or germ cells (44 + X + Y) divide mitotically, to give rise to more spermatogonia of type A, and also to spermatogonia of type B.

(B) The Spermatogonia (type B) (44 + X + Y) enlarge, or undergo mitosis, to form primary spermatocytes.

(C) The Primary spermatocytes (44 + X + Y) now divide so that each of them forms two secondary spermatocytes. This is the first meiotic division:

(D) Each secondary spermatocyte has 22 + X or 22 + Y chromosomes. It divides to form two spermatids. This is the second meiotic division and this time there is no reduction in chromosome number.

(E) Each spermatid (22 + X or 22 + Y) gradually changes its shape to become a spermatozoon. This process of transformation of a circular spermatid to a spermatozzon is called spermiogenesis.

OOGENESIS

The female gonad is the ovary. It has an outer part called the corte and an inner part, the medulla. The cortex contains many large round cells called oogonia. All the oogonia to be used throughout the life of a woman are produced at a very early stage (possibly before birth) and do not multiply thereafter.

Ova are derived from oogonia as how similar the process is to spermatogenesis. However, there are important differences as well.

(i) Observe that whereas one primary spermatocyte gives rise to four spermatozoa, one primary oocytei forms only one ovum.

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(ii) When the primary spermatocyte divides, its cytoplasm is equally distributed between the two secondary spermatocytes formed. However, when the primary oocyte divides, almost all its cytoplasm goes to the daughter cell which forms the secondary oocyte. The other daughter cell (first polar body), receives half the chromosomes of the primary oocyte, but almost no cytoplasm. The first polar body is, therefore, formed merely to get rid of unwanted chromosomes.

In the immature female, many oogonia become primary oocytes and enter the first meiotic division. However, this division does not progress beyond the diplotene stage of prophase, because of the presence of an oocyte maturation inhibitor (OMI) secreted by follicular cells surrounding the oocyte. The formation of germ cells (oogonia and primary occytes) begins during intrauterine life. The ovary of a five month old fetus may contain as many as seven million germ cells. Thereafter, many of them degenerate, and by the time the fetus reaches full term the number may be about two million. By puberty (when ovulation begins) only about 40,000 oocytes are left in the ovary. This number is ample considering the fact that mature woman shed only about 500 ova in her life time.

SEX DETERMINATION

It will be seen that all ova contain 22 + X chromosomes. However, we have seen that spermatozoa are of two types. Half of them have 22 + X chromosomes and the other half of them have 22 + Y chromosomes. We speak of these as ‘X-bearing’, or ‘Y-bearing’, spermatozoa. An ovum can be fertilized by either type of spermatozzon. If the sperm is X-bearing, the zygote has 44 + X + X chromosomes and the offspring is a girl. If the sperm is Y-bearing, the zygote has 44 + X + Y chromosomes and the offspring is a boy. Thus the sex of a child is ‘determined’ at the time of fertilization. It will now be clear that, as stated earlier, one chromosome of each of the 23 pairs is derived from the mother and the other from the father.

STRUCTURE OF A MATURE SPERMATOZZON

The spermatozoon has a head, a neck, a middle piece and a principal piece or tail. The head is covered by a cap-like structure called the acrosome (also called the acrosomic cap, or galea capitis). The neck is narrow: it contains a funnel-shaped basal body and a spherical centriole. An axial filament begins just behind this centroile: it passes through the middle piece and extends into the tail. At the point where the middle piece joins the tail, this axial filament passes through a ring-lke structure called the annulus. That part of the axial filament which

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lies in the middle piece, is surrounded by a spiral sheath made up of mitochondria.

The headof the human spermatozoon is flattended from before backwards so that it is oval when seen from the front but appears to be pointed (somewhat like a spear-head) when seen from one side, or in section. It consists of chromatin (mostly DNA) that is extremely condensed and, therefore, appears to have a homogeneous structure even when examined by a electron microscope. This condensation makes it highly resistant to various physical stresses.

The chief structure to be seen in the neck is the basal body. It is also called the connecting piece because it helps establish an intimate union between the head and the remainder of the spermatozoon. The basal body is made up of nine segmented rod like structures each of which is continuous distally with one coarse fibril of the axial filament. On its proximal side (i.e., towards the head of the spermatozoon) the basal body has a convex articular surface which fits into a depression (implantation fossa) in the head.

The axial filament, that passes through the middle piece and most of the tail, is really composed of several fibrils arranged as illustrated. There is a pair of central fibrils, surrounded by nine pairs (doublets) arranged in a circle around the central pair (This arrangement of one central pair of fibrils surrounded by in doublets is interesting in that exactly the same arrangement is to be seen in cilia; compare also with the structure of centriole). In addition to these doublets there are nine coarser petal-shaped fibrils of unequal size, one such fibril lying just outside each doublet. These coarse fibrils are present in the middle piece and most of the tail but do not extend into the terminal part of the tail. The whole system of fibrilsis kept in position by a series of coverings. Immediately outside the fibrils there is a fibrous sheath. In the region of the middle piece the fibrous sheath is surrounded by spirally arranged mitochondria. Finally, the entire sperm is enclosed in a plasma membrane.

It will be seen that one of the coarse fibrils is large than the others. This is called fibril 1, the others being numbered proceeding in a clockwise direction form it. The fibrous sheath is adherent to fibrils 3 and 8. The line joining fibrils 3 and 8 divides the tail into a major compartment containing 4 fibrils and a minor compartment containing 3 fibrils. This line also passes through both the central fibrils and provides an axis with reference to which sperm movements can be analysed.

Maturation and Capacitation of Spermatozoa

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As fully formed spermatozoa pass through the male genital passages they undergo a process of maturation. Spermatozoa acquire some motility only after passing through the epididymis. The secretions of the epididymis, seminal vesicles and the prostate have a stimulating effect on sperm motility, but the spermatozoa become fully motile only after ejaculation. When introduced into the vagina, spermatozoa reach the uterine tubes much sooner than their own motility would allow, suggesting that contractions of uterine and tuba) musculature exert a sucking effect.

Spermatozoa acquire the ability to fertilize the ovum only after they have been in the female genital tract for some time. This final step in their maturation is called capacitation. During capacitation some proteins and glycoproteins are removed from the plasma membrane overlying the acrosome. When the sperm reaches near the ovum, changes take place in membranes over the acrosome and enable release of lysosomal enzymes present within it. This is called the acrosome reaction. The substances released include hyaluronidase which helps in separating corona radiata cells present over the ovum. Trypsin like substances, and a substance called acrosin, help in digesting the zona pellucida and penetration of the sperm through it. Changes in the properties of the zona pellucida constitute the zona reaction.

Spermiogenesis

The process by which a spermatid becomes a spermatozoon is called spermiogenesis (or spermateleosis). The spermatid is a more or less circular cell containing a nucleus, Golgi apparatus, centriole and mitochondria. All these components take part in forming the spermatozoon. The nucleus forms the head. The Golgi apparatus is transformed into the acrosomic cap. The centriole divides into two parts which are at first close together: the axial filament appears to grow out of them. One centriole becomes spherical and comes to lie in the neck. According to some workers, the other centriole forms the basal body, but according to some others it forms the annulus. The part of the axial filament between the head and the These flattened cells ultimau*annulus, becomes surrounded by mitochondria, and together with them forms the cells.

Formation of Ovarian Follicles

We have seen that ova develop from oogonia present in the cortex of the ovary. The oogonia are surrounded by other cells that form a groundwork (or stroma) for them. These stromal cells form the ovarian or Graafian follicle that surrounds the ovum and protects it. The stages in the formation of the follicle are as follows:

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(1) Some cells of the stroma become flattened and surround an oocyte. These flattened cells ultimately form the ovarian follicle and are, therefore, called follicular cells.

(2) The flattened follicular cells become collumnar. Follicles upto this stage of development are called primordial follicles.

(3) A homogeneous membrane, the zona pellucida, appears between the follicular cells and the oocyte.

(4) The follicular cells proliferate to form several layers of cells which constitute the membrana granulosa. The cells may now be called granulosa cells.

(5) A cavity (or antrum) appears within the membrana granulosa. With its appearance a follicle is formed (follicle = small sac).

(6) The cavity of the follicle rapidly increases in size. As a result, the wall of the follicle (formed by the granulosa cells) becomes relatively thin. The oocyte now lies eccentrically in the follicle, surrounded by some granulosa cells that are given the name cumulus oophoricus (or cumulus ovaricus). The cells that attach it to the wall of the follicle are given the name discus proligerus.

(7) As the follicle expands, the stromal cells surrounding the membrana granulosa become condensed to form a covering called the theca interna (theca = cover). The cells of the theca interna later secrete a hormone called oestrogen; and they are then called the cells of the thecal gland.

(8) Outside the theca interna some fibrous tissue becomes condensed to form another covering for the follicle called the theca externa. The ovarian follicle is now fully formed.

Ovulation

The shedding of the ovum from the ovary is called ovulation. The ovarian follicle is at first very small compared to the thickness of the cortex of the ovary. As it enlarges, it becomes so big that it not only reaches the surface of the ovary, but also forms a bulging in this situation. Just before ovulation it may have a diameter of 15 mm. The stroma and theca on this side of the follicle become very thin. An avascular area (stigma) appears over the most convex point of the follicle. At the same time, the cells of the cumulus oophoricus become loosened by accumulation of intercellular fluid between them. Ultimately, the follicle ruptures and the ovum is shed from the ovary.

Structure of the Ovum

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The ovum that is shed from the ovary is not fully mature. It is really a secondary oocyte which is undergoing division to shed off the second polar body (see p. I I). At this stage the ovum has the appearance illustrated in Fig. 2.13. Note that it is surrounded by the zona pellucida. Some cells of the corona radiata can be seen sticking to the outside of the zona pellucida. No nucleus is seen, as the nuclear membrane has dissolved for the second meiotic division. A spindle is, however, present. Between the cell membrane (or vitelline membrane) and the zona pellucida, a distinct space (perivitelline space) is seen. In it lies the first polar body, which separates from the ovum during the first meiotic division. Note that the ovum is a very large cell and measures more than 100 µm in diameter. In contrast most other cells of the body measure less than 10µm. (One µm is one thousandth of a millimetre).

Fate of the Ovum

Let us see what happens to the ovum that is shed from the ovary. You already know that the ovary is closely embraced by the fimbriated end of the uterine tube. So the ovum is easily carried into the tube partly by the follicular fluid discharged from the follicle and partly by the activity of ciliated cells lining the tube. The ovum slowly travels through the tube towards the uterus, taking three to four days to do so. If sexual intercourse takes place at about this time, the spermatozoa deposited in the vagina swim into the uterus and from there into the uterine tube. One of these spermatozoa may fertilize the ovum. If this happens, the fertilized ovum begins to develop into an embryo. It travels to the uterus and gets implanted in its wall. On the other hand if the ovum (secondary oocyte) is not fertilized it dies in 12 to 24 hours. It passes through the uterus into the vagina and is discharged.

Corpus Luteum

The corpus luteum is an important structure. It secretes a hormone progesterone. The corpus luteum is derived from the ovarian follicle, after the latter has ruptured to shed the ovum, as follows:

(a) When the follicle ruptures, its wall collapses and becomes folded.

(b) At this stage, the follicular cells are small and rounded (Fig. 2.15A). They now rapidly enlarge. As they increase in size their walls press against those of neighbouring cells so that the cells acquire a polyhedral shape (Fig. 2.1513). Their cytoplasm becomes filled with a yellow pigment called lutein. They are now called luteal cells. The presence of this yellow pigment gives the structure a yellow colour and that is why it is called the corpus luteum (yellow body). Some cells of the theca internal also enlarge and contribute to the corpus luteum.

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(c) We have seen that the corpus luteum secretes progesterone. This secretion has to be poured into the blood like secretions of endocrine glands. All endocrine glands are richly supplied with blood vessels for this purpose. The ovarian follicle itself has no blood vessels, but the surrounding theca interna is full of them. When the corpus luteum is forming, blood vessels form the theca interna invade it and provide it with a rich supply of blood.

The subsequent fate of the corpus luteum depends on whether the ovum is fertilized or not.

(i) If the ovum is not fertilized, the corpus luteum persists for about 14 days. During this period it secretes progesterone. It remains relatively small and is called the corpus luteum of menstruation. At the end of its functional life, it degenerates and becomes converted into a mass of fibrous tissue called the corpus albicans (white body).

(ii) If the ovum is fertilized and pregnancy results, the corpus luteum persists for three to four months. This is larger than the corpus luteum of menstruation, and is called the corpus luteum of pregnancy. It may occupy one third to half of the total volume of the ovary. The progesterone secreted by it is essential for the maintenance of pregnancy in the first few months. After the fourth month, the corpus luteum is no longer needed, as the placenta begins to secrete progesterone. Degeneration of the corpus luteum in the early months of pregnancy is prevented by chorionic gonadotropin (hCG) secreted by the trophoblast cells of the developing embryo.

The series of changes that begin with the formation of an ovarian follicle and end with the degeneration of the corpus luteum constitute what is called an ovarian cycle.

Fate of Ovarian Follicles

We have seen that in each ovarian cycle one follicle reaches maturity, sheds an ovum, and becomes a corpus luteum. At the same time, several other follicles also begin to develop, but do not reach maturity. It is interesting to note that, contrary to what one might expect, these follicles do not persist into the next ovarian cycle, but undergo degeneration. The ovum and granulosa cells of each follicle disappear. The cells of the theca interna, however, proliferate to form the interstitial glands, also called the corpora atretica (singular = cropus atreticum). These glands are believed to secrete oestrogens. After a period of activity, each gland becomes a mass of scar tissue indistinguishable from the corpus albicans formed from the corpus

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luteum.

Ovarian Cycle and Hormones

The changes taking place during the ovarian cycle are greatly influenced by certain hormones produced by the hypophysis cerebri (see p. 30). The hormones produced by the theca interna and by the corpus luteum in turn influence other parts of the female reproductive system—notably the uterus, resulting in a cycle of changes referred to as the uterine or menstrual cycle.

Reproductive Period

In an individual the formation of gametes takes place only during the reproductive period which begins at the age of puberty (10 to 14 years). In women it ends between 45 and 50 years, but in men it may continue till the age of 60 years or more.

Abnormalities in Formation of Gametes

(a) Abnormalities of form: Spermatozoa may be too large (giant) or too small (dwarf). The head, body or tail may be duplicated. The ovum may have an unusually large nucleus or two nuclei. Two oocytes may be seen in one follicle.

(b) Chromosomal abnormalities: The gametes may be abnormal in chromosomal content as follows:

(i) During the first meiotic division, the two chromosomes of a pair, instead of separating at anaphase, may both go to the same pole (This is called non-disjunction). The resulting gamete then has 24 chromosomes instead of the normal 23. At fertilization by this gamete, the zygote will, therefore, have 47 chromosomes; there being three identical chromosomes instead of one of the normal pairs. This is called trisomy. Depending upon the particular chromosomes involved, various abnormalities are produced.

Trisomy of chromosome 21 results in a condition called mongolism or Down's syndrome. In this condition the child has a broad face, obliquely placed palpebral fissures, epicanthus, a furrowed lower lip, and broad hands with a single transverse crease. Usually the patients are mentally retarded, and have anomalies of the heart.

The presence of an extra X or Y chromosome can give rise to various syndromes associated with abnormal genital development, mental retardation and abnormal growth. Some of these are: XXX— abnormal female; XXY — Klinefelter's syndrome abnormal male; XYY — abnormal male.

In Klinefelter's syndrome the subject is a male (because of the

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presence of a Y chromosome). However, the testes are poorly developed leading to sterility and gynaecomastia.

Patients anents with XXX chromosomes show two masses of sex chromatin in their and are sometimes referred to as 'super females'. However, there is nothing i4vr' about them. In fact their bodies show poor sexual development (i.e., they we infantile) and menstruation is scanty. Mental retardation is usual.

(ii) When both chromosomes of a pair go to one gamete (as described above), the other gamete resulting from the division has only 22 chromosomes; and at fertilization the zygote has only 45 chromosomes. Hence one pair is represented by a single chromosome. This is called monosomy.

The best known example of this is a female with only one X chromosome I Turner's syndrome). In this syndrome the subject is always female (because of absence of a Y chromosome). There is agenesis of ovaries. Associated deformities include mental retardation, skeletal abnormalities, and folds of skin on the sides of the neck (webbed neck).

(iii) Such anomalies may affect more than one pair of chromosomes. Alternatively, one pair may be represented by more than three chromosomes; when this happens with the sex chromosomes, individuals with the constitution XXXY, XXXXY, XXYY, or XXXX may be produced.

(iv) Sometimes a gemete may have the diploid number of chromosomes so that the zygote will have 46 + 23 (i.e., 69) chromosomes. This is called triploidy. Higher multiples of 23 may also be seen; such fetuses are generally born dead.

(v) Abnormalities in the process of crossing over can result in a number of chromosomal abnormalities as follows:

(a) Part of a chromosome may get attached to a chromosome of a different pair (translocation).

(b) Part of a chromosome may be lost (deletion).

(c) The two chromosomes of a pair may break at unequal distances; when each piece joins the opposite chromosome, one chromosome is longer than normal and some of the genes are duplicated. The other chromosome will be shorter than normal, some genes being missing.

(d) A piece separating from a chromosome may get inverted before joining the opposite chromosome (inversion). Although

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the same genes are present, their sequence is disturbed.

(vi) We have seen that during cell division the centromere splits longitudinally so that each chromatid becomes a separate chromosome. Sometimes the centromere splits transversely producing two dissimilar chromosomes; one chromosome is made up of the short arms of both chromatids, while the other is made up of the long arms. Such chromosomes are called isochromosomes.

Chromosomal errors of the types described above may also occur during segmentation of the ovum (Chapter 4). This results in a fetus having a mixture of cells with normal and abnormal chromosomes. This is called niosaicisni. Such individuals may also show various abnormalities.

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3The Uterine (Menstrual) Cycle

While the changes concerned with ovulation, and the formation of the corpus luteum, are going on in the ovary, the uterine endometrium shows striking cyclical changes. These cyclical changes constitute the uterine, or menstrual cycle. The most prominent feature of this cycle is a monthly flow of blood from the uterus. This is called menstruation, or menses. A menstrual cycle is taken to begin with the onset of menstrual bleeding and ends just before the next menstruation.

The various structures that go to make up the uterine endometrium are illustrated in. The surface of the endometrium is lined by a columnar epithelium. The stroma contains numerous simple tubular glands. The arteries that supply the endometrium tend to run vertically towards the surface. Some of these run spirally and supply the whole thickness of the endometrium, while others that remain straight are confined to the basal part. All these structures are concerned with the changes occurring during the menstrual cycle.

PHASES OF THE MENSTRUAL CYCLE

The menstrual cycle is usually divided into the following phases, on the basis of changes taking place in the uterine endometrium (Fig. 3.3):

(a) Post-menstrual.(b) Proliferative.(c) Secretory or pre-menstrual.(d) Menstrual.

The changes during the post-menstrual phase and during most of the proliferative phase take place under the action of oestrogens produced by the developing follicles in the ovary. Hence this period is referred to as the follicular phase of the menstrual cycle. The follicular phase constitutes the first half of the menstrual cycle. Following ovulation, the corpus luteum is formed and starts secreting progesterone. During the second half of the menstrual cycle, this hormone (along with oestrogens) produces striking changes in the endometrium. As these changes take place under the influence of the corpus luteum, this half of the menstrual cycle is called the luteal phase. Just before the onset of the next bleeding, there is lowering of levels of both progesterone and oestrogens, and it is believed that this

21

'withdrawal' leads to the onset of menstrual bleeding.

The division of the menstrual cycle into the phases mentioned above is, however, arbitrary. The changes are really continuous, and may be summarized as follows:

(1) The endometrium progressively increases in thickness (Fig. 3.4). In the post-menstrual phase it is 0.5 to 1 mm thick; in the proliferative phase it is 2 to 3 mm thick; and in the secretory phase its thickness reaches 5 to 7 mm.

The uterine glands grow in length. At first they are straight, but gradually become convoluted. Because of these convolutions, the glands acquire a 'saw-toothed' appearance when seen in longitudinal section. The glands also increase in diameter. The most basal parts of uterine glands, however, remain tubular and do not undergo these changes.

(2) The epithelim lining the glands is at first coboidal. During the proliferative stage it becomes columnar. Glycogen accumulates in the basal portion of the epithelial cell, pushing the nucleus nearer the lumen. During the secretory phase the apical part of the cell is shed off as part of the secretion. The cell again becomes cubical, but the edge towards the lumen becomes irregular.

(4) During the post-menstrual phase, the cell of the stroma are uniformly distributed and are compacty arranted. As the endometrium increases in thickness (during the proliferative phase), the superficial part of the stroma remains compact, but the part surrounding the bodies of the uterine glands becomes spongy. The deepest part of the stroma also remains compact. The stroma can, therefore, be divided into the following three layers.

(a) Stratum compactum.

(b) Stratum spongiosum.

(c) Stratum basale.

During the secretory phase, these layers become better defined. The endometrium becomes soft and oedematous, because of the fluid secreted by the uterine glands. (5) The arteries of the endometrium are small to begin with. They grow in length during the proliferative phase. During the secretory phase, the arteries supplying the superficial two-thirds of the endometrium become very tortuous, and are called spiral arteries. The arteries to the basal third of the endometrium (which does not participate in the changes associated with the menstrual cycle) remain straight and short.

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Towards the end of the secretory phase the endometrium is thick, soft, and richly supplied with blood. The secretory activity of the uterine glands not only makes the endometrium soft, but also provides nutrition to the embryo. These changes are, therefore, an obvious preparation for providing a suitable environment for the fertilized ovum, when it reaches the uterus. In the absence of pregnancy, however, these measures are abortive: the superficial parts of the thickened endometrium (stratum compactum and stratum spongiosum) are shed off, and this is accompanied by menstrual bleeding. A few hours before the onset of menstrual bleeding the spiral arteries get constricted so that blood supply to superficial parts of the endometrium is cut off. This ischaemia leads to degeneration of the endometrium and also damages the walls of the blood vessels themselves. Subsequently when the arteries relax and blood again flows into the endometrium it leaks out through the damaged blood vessels. This leaking blood causes the endometrium to be shed off bit by bit, and the blood along with shreads of endometrium flows out through the vagina. At the end of menstruation, the endometrium that remains is only 0.5 mm thick. It consists of the stratum hasale along with the basal portions of the uterine glands (Fig. 3.613). The epithelium of these glands rapidly proliferates and reforms the lining epithelium.

The endometrial changes associated with the menstrual cycle are confined to the body of the uterus. The cervical mucosa is not affected.

Time of Ovulation in Relation to Menstruation

In a 28-day menstrual cycle, ovulation takes place at about the middle of the cycle. The period between ovulation and the next menstrual bleeding is constant at about 14 days, but the time of ovulation does not have a constant relationship with the preceding menstruation. This is so because the length of the menstrual cycle may vary from month to month in an individual. Hence, it is difficult to predict the date of the next ovulation from the date of menstruation unless the woman has very regular menstrual periods.

There are many methods of finding out the exact time of ovulation, but the one commonly used is the temperature method. In this technique, the woman's temperature is recorded every morning. When these temperatures are plotted on a graph, we get a curve like that shown in Fig. The temperature is low during actual menstruation. Subsequently it rises. At about the middle of the cycle, there is a sudden fall in temperature followed by a rise. This rise is

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believed to indicate that ovulation has occurred.

Importance of Determining the Time of Ovulation

After ovulation, the ovum is viable (i.e., it can be fertilized) for not more than two days. Spermatozoa introduced into the vagina die within four days. Therefore, fertilization can occur only if intercourse takes place during a period between four days before ovulation to two days after ovulation. The remaining days have been regarded as a 'safe period' as far as prevention of pregnancy is concerned. This forms the basis of the so-called 'rhythm-method' of family planning. The method has, however, not proved reliable because of variability in the length of the cycle. It has also been shown that various factors (e.g., emotional stress) may precipitate, or delay, ovulation.

Knowledge regarding the time of ovulation is also of importance in cases of sterility (difficulty in having children), where the couple can be advised to have intercourse during the days most favourable for conception.

In some women, ovulation is accompanied by slight pain. As this pain occurs approximately midway between two menstrual periods it is referred to as middle Pain.

Hormones Influencing Ovulation and Menstruation

We have seen that the changes taking place in the uterine endometrium during the menstrual cycle occur under the influence of:

(a) oestrogens produced by the theca] gland (theca interna) and by the interstitial gland cells (pp. 18, 21), and possibly by granulosa cells.

(b) progesterone produced by the corpus luteum.

The development of the ovarian follicle, and of the corpus luteum, is in turn dependent on hormones produced by the anterior lobe of the hypophysis cerebri. These are:

(i) the follicle stimulating hormone (FSH) which stimulates the formation of follicles and the secretion of oestrogen; and

(ii) the luteinizing hormone (LH) which helps to convert the ovarian follicle into the corpus luteum and stimulates the secretion of progesterone. Secretion of FSH and LH is controlled by a gonadotropin releasing hormone (GnRH) produced by the hypothalamus. Production of LH is also stimulated by feedback of oestrogens secreted by follicular cells of the ovary. A sudden increase (surge) in the level of LH takes place near the middle of the cycle and stimulates ovulation which takes place about 36

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hours later. Apart from hormones, nervous and emotional influences may affect the ovarian and menstrual cycles. An emotional disturbance may delay or even prevent menstruation.

Use of Hormones for Contraception

Ovulation in a woman (and by corollary, pregnancy) can be prevented by administration of contraceptive pills. The most important ingredients of such pills are progestins (in the form of synthetic compounds). Better results are obtained when a small amount of oestrogen is also given. Stoppage of the pill reduces levels of these hormones in blood and this withdrawal leads to menstrual bleeding. Such pills have almost 100 per cent success in suppressing maturation of follicles and ovulation.

In the most common variety of pill (distributed by government agencies in India) the progestin is norethisterone acetate ( I mg); and the oestrogen is in the form of oestradiol (50 yg). The pills are distributed in packets, each of which contains 21 pills having these hormones, and 7 pills without hormones (for the last 7 days). Pills are started 5 days after menstruation. Normal menstruation occurs during the 7 days in which pills without hormones are being taken. If the pills are taken regularly there is a regular menstrual cycle of 28 days duration.

Conception can also be prevented by implantation of progestin under the skin. Such implants can prevent pregnancy for up to 5 years.

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4Formation of Germ Layers & Embryonic Disc

FERTILIZATION

In Chapter 2 we have seen that while the ovarian follicle is growing, the oogonium within it undergoes maturation. The oogonium enlarges to form a primary oocyte. The primary oocyte undergoes the first meiotic division to shed off the first polar body and becomes a secondary oocyte. At the time of ovulation, the second meiotic division is in progress and a spindle has formed for separation of the second polar body (Fig. 4.2B). At this stage the 'ovum' enters the infundibulum of the uterine tube and passes into the ampulla.

Fertilization of the ovum occurs in the ampulla of the uterine tube. One spermatozoon pierces the zona pellucida and enters the ovum. When a spermatozoon comes in contact with the oocyte, plasma membranes of the two cells fuse. This, probably occurs at receptor sites that are specific for a species. Both the head and tail of the spermatozoon (excluding the plasma membrane) enter the cytoplasm of the ovum.

Entry of a sperm into the oocyte leads to the following changes.

(a) Alterations taking place in the plasma membrane of the oocyte, and in the zona pellucida, ensure that no other spermatozoon can enter the oocyte.

(b) The second meiotic division (which was thus far incomplete) is completed, and the second polar body is extruded.

The chromosomes of the ovum now assume the shape of a nucleus called the female pronucleus. At the same time the head of the spermatozoon (which it will be remembered is formed from the nucleus) separates from the middle piece and tail, and transforms itself into the male pronucleus. Entry of the sperm leads to metabolic changes within the ovum that facilitate its development into an embryo.

The male and female pronuclei meet, but they do not fuse to form one nucleus. Their nuclear membranes disappear and their chromosomes become distinct. It will be recalled that each pronucleus has 23 chromosomes so that the fertilized ovum now has 46 chromosomes in all. However, as the pronuclei have single complements of DNA, replication of DNA takes place in the

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chromosomes derived from each pronucleus. Each of the 46 chromosomes then splits into two. Meanwhile, a spindle has formed, and one chromosome of each pair moves to each end of the spindle (as in mitosis), leading to the formation of two daughter cells. This is called the two-cell stage of the embryo. Note that strictly speaking there is no one-cell stage of the embryo.

The important points to note at this stage are that:

(i) the two daughter cells are still surrounded by the zona pellucida;

(ii) each daughter cell is much smaller than the ovum. As subsequent divisions occur, the cells become smaller and smaller until they acquire the size of most cells of the body.

From what has been said above, it will be clear that as a result of fertilization:

(a)the diploid chromosome number is restored;

(b)determination of sex takes place; and

(c) the fertilized ovum begins to divide into several cells (i.e., it undergoes cleavage).

TEST TUBE BABIES

The so called test tube babies are produced by the technique of in vitro fertilization. (In vitro = outside the body, as against in vivo = within the body). This technique is being increasingly used in couples who are not able to achieve fertilization in the normal way.

Gonadotropins are administered to the woman to stimulate growth of follicles in the ovary. Just before ovulation, the ovum is removed (using an aspirator) and is placed in a suitable medium. Spermatozoa are added to the medium. Fertilization and early development of the embryo take place in this medium. The process is carefully monitored, and when the embryo is at the 8-cell stage it is put inside the uterus. Successful implantation takes place in about 20 per cent of such trials.

Cleavage

The two cells formed as described above undergo a series of divisions. One cell divides first so that we have a '3-cell' stage of the embryo (Fig. 4.413) followed by a '4-cell' stage (Fig. 4.4C), a '5-cell' stage, etc. This process of subdivision of the ovum into smaller cells is called cleavage.

As cleavage proceeds the ovum comes to have 16 cells. It now looks like a mulberry and is called the morula (Fig. 4.41)). It is still

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surrounded by the zona pellucida. If we cut a section across the morula, we see that it consists of an inner cell mass that is completely surrounded by an outer layer of cells. The cells of the outer layer will later give rise to a structure called trophobalast.

The inner cell mass gives rise to the embryo proper, and is, therefore, also called the embryoblast. The cells of the trophoblast help to provide nutrition to the embryo.

Some fluid now passes into the morula from the uterine cavity, and partially separates the cells of the inner cell mass from those of the trophoblast (Fig. 4.513). As the quantity of fluid increases, the morula acquires the shape of a cyst. The cells of the trophoblast become flattened, and the inner cell mass comes to be attached to the inner side of the trophoblast on one side only (Fig. 4.5Q. The morula has now become a blastocyst. The cavity of the blastocyst is the blastocoele. That side of the blastocyst to which the inner cell mass is attached is called the embryonic or animal pole, while the opposite side is the abembryonic pole.

Function of the Zona Pellucida

The trophoblast has the property of being able to stick to the uterine (or other) epithelium and its cells have the capacity to eat up other cells. They can, therefore, invade and burrow into tissues with which they come in contact. As the embryo travels down the uterine tube, and the uppermost part of the uterine cavity, it is prevented from 'sticking' to the epithelium by the zona pellucida. During this time it receives nutrition, partly from the substances stored within the ovum (e.g., yolk), and partly by diffusion from the uterine secretions. By the time a blastocyst is formed, it is necessary for the embryo to acquire additional sources of nutrition. This is achieved when the blastocyst 'sticks' to the uterine endometrium, and gets implanted in it. However, before this can happen, it is necessary for the zona pellucida to disappear. The zona pellucida disappears soon after the morula reaches the uterine lumen. Thus, the function of the zona pellucida is to prevent implantation of the blastocyst at an abnormal site.

ABNORMAL EMBRYOS

Sometimes embryos formed as a result of fertilization are abnormal. Some of their cells degenerate, and the blastomeres may be multinucleated. Most such embryos die within two to three weeks and a woman may not even become aware of such a pregnancy. According to some estimates as many as 50 per cent of embryos may be aborted in this way. This may be nature's mechanism to get rid of defective embryos.

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FORMATION OF GERM LAYERS

As the blastocyst develops further, it gives rise not only to the tissues and organs of the embryo but also to a number of structures that support the embryo and help it to acquire nutrition. At a very early stage in development, the embryo proper acquires the form of a three-layered disc. This is called the embryonic disc (also called embryonic area, embryonic shield, or germ disc).

The three layers that constitute this embryonic disc are:

(1) Endoderm (endo = inside)

(2) Ectoderm (ecto = outside)

(3) Mesoderm (meso = in the middle)

These are the three germ layers. All tissues of the body are derived from one or more of these layers (Chapter 20). Much of the student's study of embryology concerns itself with learning from which of these germ layers particular tissues and organs develop. In the further development of the blastocyst that we will now consider, it is very important to have a clear conception of the formation of germ layers and of their fate.

We have seen that the blastocyst is a spherical cyst lined by flattened trophoblastic cells, and that inside it there is a mass of cells, the inner cell mass, attached eccentrically to the trophoblast. Further changes are as follows:

(a) Some cells of the inner cell mass differentiate (i.e., they become different from others) into flattened cells, that come to line its free surface. These constitute the endoderm, which is thus the first germ layer to be formed.

(b) The remaining cells of the inner cell mass become columnar (Fig. 4.6B). These cells form the second germ layer, the ectoderm. The embryo is now in the form of a disc having two layers.

(c) A space appears between the ectoderm (below) and the trophoblast (above). This is the amniotic cavity (Fig. 4.6Q, filled by amniotic fluid, or liquor amnii. The roof of this cavity is formed by amniogenic cells derived from the trophoblast, while its floor is formed by the ectoderm.

(d) Flattened cells arising from the endoderm (or, according to some, from trophoblast), spread and line the inside of the blastocystic cavity (This lining of flattened cells is called Heuser's membrane). In this way, a cavity, lined on all sides by cells of

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endodermal origin, is formed. This cavity is called the primary yolk sac.

(e) The cells of the trophoblast give origin to a inass of cells called the extra-embryonic mesoderm (or primary mesoderm). These cells come to lie between the trophoblast and the flattened endodermal cells lining the yolk sac, thus separating them from each other. These cells also separate the wall of the amniotic cavity from the trophoblast.

This mesoderm is called 'extra-embryonic' because it lies outside the embryonic disc. It does not give rise to any tissues of the embryo itself.

(f) Small cavities appear in the extra-embryonic mesoderm. Gradually these join together to form larger spaces and, ultimately, one large space is formed. This cavity is called the extra-embryonic coelom (also called the chorionic cavity). With its formation, the extra-embryonic mesoderm is split into two layers. The part lining the inside of the trophoblast, and the outside of the amniotic cavity, is called the parietal or somatopleuric extra-embryonic mesoderm (It is also referred to as the chorionic plate). The part lining the outside of the yolk sac is called the visceral or splanchnopleuric extra-embryonic mesoderm. From it will be seen that the extra-embryonic coelom does not extend into that part of the extra-embryonic mesoderm which attaches the wall of the amniotic cavity to the trophoblast. The developing embryo, along with the amniotic cavity and the yolk sac, is now suspended in the extra-embryonic coelom, and is attached to the wall of the blastocyst (i.e., trophoblast) only by this unsplit part of the extra-embryonic mesoderm. This mesoderm forms a structure called the connecting stalk.

(g) Formation of Chorion and Amnion: At this stage, two very important membranes are formed. One is formed by the parietal extra-embryonic mesoderm (on the inside) and the overlying trophoblast (on the outside); this is called the chorion. The other is the amnion which is constituted by amniogenic cells forming the wall of the amniotic cavity (excluding the ectodermal floor). These cells are derived from the trophoblast. We have already seen that the amnion is covered by the parietal extra-embryonic mesoderm, and that the connecting stalk is attached to it.

The chorion and amnion play an important role in child birth (parturition) and we will refer to them again.

(h) With the appearance of the extra-embryonic mesoderm, and later

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of the extra-embryonic coelom, the yolk sac becomes much smaller than before and is now called the secondary yolk sac. This alteration in size is accompanied by a change in the nature of the lining cells. They are no longer flattened but become cubical.

(i) At this stage, the embryo proper is a circular disc composed of two layers of cells: the upper layer (towards amniotic cavity) is the ectoderm, the cells of which are columnar, while the lower layer (towards yolk sac) is the endoderm, made up of cubical cells. There is no indication yet of a head or tail end of the embryonic disc.

(j) However, we soon see that, at one circular area near the margin of the disc, the cubical cells of the endoderm become columnar. This area is called the prochordal plate. The appearance of the prochordal plate determines the central axis of the embryo (i.e., enables us to divide it into right and left halves), and also enables us to distinguish its head and tail ends.

(k) Soon after the formation of the prochordal plate some of the ectodermal cells lying along the central axis, near the tail end of the disc, begin to proliferate, and form an elevation that bulges into the amniotic cavity. This elevation is called the primitive streak. The primitive streak is at first a rounded or oval swelling, but with elongation of the embryonic disc it becomes a linear structure lying in the central axis of the disc.

(l) The cells that proliferate in the region of the primitive streak pass sideways, pushing themselves between the ectoderm and endoderm (Fig. 4.11). These cells form the intra-embryonic mesoderm (or secondary mesoderm) which is the third germ layer (According to some workers, the prochordal plate-and the neural crest also form some intra-embryonic mesoderm). The process of formation of the primitive streak, and of intra-embryonic mesoderm by the streak, is referred to as gastrulation.

(m) The intra-embryonic mesoderm spreads throughout the disc except in the region of the prochordal plate. Note that the mesoderm extends cranial to the prochordal plate, and here mesoderm from the two sides becomes continuous across the midline (Fig. 4.12). In the region of the prochordal plate, the ectoderm and endoderm remain in contact. In later development, the ectoderm and endoderm mostly persist as a lining epithelium. On the other hand, the bulk of the tissues of the body is formed predominantly from mesoderm. As there is no mesoderm in the prochordal plate, this region remains relatively thin, and later forms the bucco-pharyngeal membrane.

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(n) The primitive streak gradually elongates, along the central axis of the embryonic disc. The disc also elongates and becomes pear-shaped.

(o) On page 37 we saw that when the embryonic disc is first formed it is suspended (along with amniotic cavity and yolk sac) from the trophoblast by the connecting stalk. To begin with, the connecting stalk is very broad compared to the size of the embryo. As the embryonic disc enlarges in size, and also elongates, the connecting stalk becomes relatively small, and its attachment becomes confined to the region of the tail end of the embryonic disc (Fig. 4.13). Some intra-embryonic mesoderm arising from the primitive streak, passes backwards into the connecting stalk. As it does so; it leaves an area caudal to the primitive streak, where ectoderm and endoderm remain in contact (i.e., mesoderm does not separate them). This region is, therefore, similar to the prochordal plate, and forms the cloaca) membrane.

ALTERNATIVE VIEW OF FORMATION OF ENDODERM

In the preceding account, the formation of germ layers conforms to classical descriptions. Some authorities describe the process differently, the main points of difference being as follows:

The layer of columnar cells (described above as ectoderm) is defined as the epiblast. The layer of cuboidal cells (described above as endoderm) is defined as the hypoblast.

Some cells of the epiblast migrate to the region of the primitive streak and form the mesoderm. Others push the hypoblast aside and form the endoderm; while those that remain form the ectoderm. Thus, according to this view, all the three germ layers are derived from the epiblast. It will be obvious that the main difference from classical description concerns the formation of endoderm.

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5Developmental Outcome of Embryonic

DiscFORMATION OF THE NOTOCHORD

The notochord is a midline structure, that develops in the region extending from the cranial end of the primitive streak to the caudal end of the prochordal plate (Figs. 4.12, 5.1, 5.2). During its development, the notochord passes through several stages which are as follows:

(a) The cranial end of the primitive streak becomes thickened. This thickened part of the streak is called the primitive knot, primitive node or Henson's node (Figs. 5.1 A, 5.2A).

(b) A depression appears in the centre of the primitive knot. This depression is called the blastopore.

(c) Cells in the primitive knot multiply, and pass cranially in the middle line, between the ectoderm and endoderm, reaching upto the caudal margin of the prochordal plate. These cells form a solid cord called the notochordal process or head process.

(d) The cavity of the blastopore now extends into the notochordal process, and converts it into a tube called the notochordal canal.

(e) The cells forming the floor of the notochordal canal become intercalated in (i.e., become mixed up with) the cells of the endoderm. The cells in the floor of the notochordal canal now separate the canal from the cavity of the yolk sac.

(f) The floor of the notochordal canal begins to break down. At first there are small openings formed in it, but gradually the whole canal comes to communicate with the yolk sac (Fig. 5.31)). The notochordal canal also communicates with the amniotic cavity through the blastopore. Thus, at this stage, the amniotic cavity and the yolk sac are in communication with each other.

(g) Gradually the walls of the canal become flattened so that instead of a rounded canal we have a flat plate of cells called the notochordal plate.

(h) However, this process of flattening is soon reversed, and the notochordal plate again becomes curved, to assume the shape of a tube (Figs. 5.3F, G). Proliferation of cells of this tube

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converts it into a solid rod of cells. This rod is the definitive (i.e., finally formed) notochord. It gets completely separated from the endoderm.

Importance of the Notochord

The notochord is present in all animals that belong to the phylum Chordata. In some of them, e.g., Amphioxus, it persists into adult life and forms the central axis of the body. In others, including man, it appears in the embryo but only small remnants of it remain in the adult. As the embryo enlarges, the primitive streak becomes inconspicuous, but the notochord elongates considerably, and lies in the midline, in the position to be later occupied by the vertebral column. However, the notochord does not give rise to the vertebral column. Most of it disappears, but parts of it persist in the region of each intervertebral disc as the nucleus pulposus.

FORMATION OF THE NEURAL TUBE

The ectoderm overlying the notochord undergoes changes that result in the formation of the neural tube. The changes are induced by the notochord. The details of the formation of the neural tube are given on page 295. For the time being, it may be noted that:

(i) The neural tube gives rise to the brain and the spinal cord.

(ii) The neural tube is formed from the ectoderm overlying the notochord and, therefore, extends from the prochordal plate to the primitive knot.

(iii) The neural tube is soon divisible into a cranial enlarged part, that forms the brain, and a caudal tubular part which forms the spinal cord.

(iv) In early embryos, the developing brain forms a large conspicuous mass, on the dorsal aspect.

The process of formation of the neural tube is referred to as neurulation.

SUBDIVISIONS OF INTRA-EMBRYONIC MESODERM

We have seen that the intra-embryonic mesoderm is formed by proliferation of cells in the primitive streak, and that it separates the ectoderm and the endoderm, except in the following regions: (a) prochordal plate (b) cloacal membrane (c) in the midline caudal to the prochordal plate, as this place is occupied by the notochord.

Cranial to the prochordal plate the mesoderm of the two sides meets in the midline. At the edges of the embryonic disc, the intra-embryonic mesoderm is continuous with the extra-embryonic mesoderm. The intraembryonic mesoderm now becomes subdivided

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into three parts.

(A) The mesoderm, on either side of the notochord, becomes thick, and is called the paraxial mesoderm.

(B) More laterally, the mesoderm forms a thinner layer called the lateral plate mesoderm.

(A) Between these two, there is a longitudinal strip of mesoderm called the intermediate mesoderm.

The paraxial mesoderm now becomes segmented into cubical masses called somitomeres which give rise to somites (also called metameres or primitive segments) (Figs. 5.5C, D). The first somites are seen on either side of the midline, a little behind the prochordal plate. More somites are formed caudally, on either side of the developing neural tube, and are seen as bulgings on the surface of the embryonic disc. The somites have an interesting history which is considered in Chapter 7. In the head region, cranial to the somites, somitomeres give origin to mesenchyme.

FORMATION OF THE INTRA-EMBRYONIC COELOM

While the paraxial mesoderm is undergoing segmentation, to form the somites, changes are also occurring in the lateral plate mesoderm. Small cavities appear in it. These coalesce (come together) to form one large cavity, called the intro-embryonic coelom. The cavity has the shape of a horseshoe (Figs. 5.6A, Q. There are two halves of the cavity (one on either side of the midline) which are joined together cranial to the prochordal plate. At first, this is a closed cavity (Fig. 5.6A) but soon it comes to communicate with the extra-embryonic coelom (Fig. 5.6C). With the formation of the intra-embryonic coelom, the lateral plate mesoderm splits into:

(i) Somatopleuric or parietal, intra-embryonic mesoderm which is in contact with ectoderm.

(i) splanchnopleuric, or visceral, intra-embryonic mesoderm which is in contact with endoderm.

The intra-embryonic coelom gives rise to pericardial, pleural, and peritoneal cavities. Their development will be considered later (page 200). For the time being note that the pericardium is formed from that part of the intra-embryonic coelom which lies, in the midline, cranial to the prochordal plate. The heart is formed in the splanchnopleuric mesoderm forming the floor of this part of the coelom (Fig. 5.7). This is, therefore, called the cardiogenic area (also called cardiogenic plate, heart forming plate). Cranial to the cardiogenic area (i.e., at the cranial edge of the embryonic disc) the

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somatopleuric and splanchnopleuric mesoderm are continuous with each other. The mesoderm here does not get split, as the intra-embryonic coelom has not extended into it. This unsplit mesoderm forms a structure called the. septum transversum.

YOLK SAC AND FOLDING OF EMBRYO

The early history of the yolk sac was traced in Chapter 4. We have seen that the primary yolk sac is bounded above by cubical endoderm of the embryonic disc, and elsewhere by flattened cells lining the inside of the blastocystic cavity. With the formation of the extra-embryonic mesoderm, and later the extra-embryonic coelom, the yolk sac becomes much smaller; it comes to be lined all round by cubical cells; and it is then called the secondary yolk sac.

The changes that now take place will be best understood by a careful study of. Note the following:

(1)There is progressive increase in the size of the embryonic disc.

(2)The head and tail ends of the disc (X, Y). however, remain relatively close together Hence, the increased length of the disc causes it to bulge upwards into the amniotic cavity.

(3)With further enlargement, the embryonic disc becomes folded on itself, at the head and tail ends. These are called the head and tail folds.

(4)With the formation of the head and tail folds, parts of the yolk sac become enclosed within the embryo. In this way, a tube lined by endoderm is formed in the embryo. This is the primitive gut, from which most of the gastrointestinal tract is derived. At first, the gut is in wide communication with the yolk sac. The part of the gut cranial to this communication is called the foregut; the part caudal to the communication is called the hindgut; while the intervening part is called the midgut (Fig. 5.8E). The communication with the yolk sac becomes progressively narrower. As a result of these changes, the yolk sac becomes small and inconspicuous, and is now termed the definitive yolk sac (also called the umbilical vesicle). The narrow channel connecting it to the gut is called the vitello-intestinal duct (also called vitelline duct. yolk stalk or omphalomesenteric duct). This duct becomes elongated and eventually disappears.

(5)As the head and tail folds are forming, similar folds are also formed on each side. These are the lateral folds. As a result, the embryo comes to be enclosed all round by ectoderm except in the region

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through which the vitello-intestinal duct is passing. Here, there is a circular aperture which may now be called the umbilical opening.

(6)As the embryonic disc folds on itself, the amniotic cavity expands greatly, and comes to surround the embryo on all sides. In this way, the embryo now floats in the amniotic fluid, which fills the cavity.

CONNECTING STALK

While discussing the formation of the extra-embryonic coelom (page 37), we saw that with the formation of this cavity the embryo (along with the amniotic cavity and yolk sac) remains attached to the trophoblast only by extra-embryonic mesoderm into which the coelom does not extend (Figs. 5.9A to Q. This extra-embryonic mesoderm forms the connecting stalk. We shall see later that the trophoblast, and the tissues of the uterus, together form an important organ, the placenta, which provides the growing embryo with nutrition and with oxygen; it also removes waste products from the embryo. The importance of the connecting stalk is obvious when we see that this is the only connecting link between the embryo and the placenta.

As the embryo grows, the area of attachment of the connecting stalk to it becomes relatively smaller. Gradually this attachment is seen only near the caudal end of the embryonic disc (Figs. 5.91), E). With the formation of the tail fold, the attachment of the connecting stalk moves (with the tail end of the embryonic disc) to the ventral aspect of the embryo. It is now attached in the region of the umbilical opening (Fig. 5.9E).

By now, blood vessels have developed in the embryo, and also in the placenta. These sets of blood vessels are in communication by means of arteries and veins passing through the connecting stalk. At first, there are two arteries and two veins in the connecting stalk, but later the right vein disappears (the left vein is 'left').

Examination of will make it clear that, at this stage, the amnion has a circular attachment to the margins of the umbilical opening, and forms a wide tube in which the following lie:

(1)Vitello-intestinal duct and remnants of the yolk sac.

(2)Mesoderm (extra-embryonic) of the connecting stalk. This mesoderm becomes converted into a gelatinous substance called Wharton's jelly. It is rich in proteoglycans and protects blood vessels in the umbilical cord.

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(3)Blood vessels that pass from the embryo to placenta.

(4)A small part of the extra-embryonic coelom.

This tube of amnion and the structures within it constitute the umbilical cord. This progressively increases in length to allow free movement of the embryo within the amniotic cavity. At the time of birth of the child, (i.e., at full term), the umbilical cord is about half a metre long, and about 2 cm in diameter. It shows marked torsion, which is probably due to fetal movements. An umbilical cord that is either too short or too long can cause problems during delivery of the fetus.

DIVERTICULUM

Before the formation of the tail fold, a small endodermal diverticulum called the allantois diverticulum arises from the yolk sac near the caudal end of the embryonic disc. This diverticulum grows into the mesoderm of the connecting stalk. After the formation of the tail fold, part of this diverticulum is absorbed into the hind-gut. It now passes from the ventral side of the hind-gut into the connecting stalk. We will refer to it again while considering the development of the urinary bladder.

EFFECT OF HEAD AND TAIL FOLDS ON POSITIONS OF OTHER STRUCTURES

Just before the formation of the liead and tail folds, the structures in the embryonic disc are oriented as shown in Fig. 5.12. A median (midline) section across the disc, at this stage, is shown in Fig. 5.13. From the cranial to the caudal side, the structures seen in the midline are the septum transversum, the developing pericardial cavity and the heart, the prochordal plate, the neural plate, the primitive streak, and the cloacal membrane. Note that the primitive streak is now inconspicuous.

After folding, the relative positions of these structures change to that shown in --igs. 5.14 and 5.15. The important points to note are as follows:

(1) With the formation of the head fold, the developing pericardial cavity comes to lie on the ventral side of the embryo, ventral to the foregut. The heart, which was developing in the splanchnopleuric mesoderm in the floor of the pericardial cavity (Fig. 5.13), now lies in the roof of the cavity (Fig. 5.14). The pericardium enlarges rapidly, and forms a conspicuous bulging on the ventral side of the embryo (Figs. 5.15, 5.16).

(2) The septum transversum (see p. 47) which was the cranialmost structure in the embryonic disc (Fig. 5.12) now lies caudal to the

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heart (Fig. 5.14). At a later stage in development, the diaphragm and liver develop in relation to the septum transversum.

(3) The region of the prochordal plate now forms the buccophan•tigeal, or oralnienibrane which closes the foregut cranially. When this membrane breaks down, the foregut communicates with the exterior.

(4) The cranialmost structure of the embryo is now the enlarged cianial part of the neural tube which later forms the brain (Fig. 5.14). This enlarges very greatly Fig. 5.15). There are now;two big bulgings on the ventral aspect of the embryo. Cranially, there is the developing brain, and a little below it there is the bulging -,ericardium (Figs. 5.15, 5.16). In between them, there is a depression called the stomatodaeum or stomodaeum, the floor of which is formed by the buccopharyngeal membrane.

(5) Towards the tail end of the embryo, the primitive streak is now an inconspicuous structure, that gradually disappears. In later life, remnants of the primitive streak may give rise to sacrococcygeal tumours that may contain tissues derived from all three germ layers. The distal end of the hindgut is closed by the cloacal membrane. At first, this is directed caudally, (Fig. 5.14) but later it comes to face entrally (Figs. 5.15, 5.16).

The effects of folding on the yolk sac, the amniotic cavity and the connecting stalk have already been considered.

We have now traced the development of the embryo to as when the stag rudiments of the nervous system, the heart and the gut have been formed. The embryo has acquired some semblance to a human body except that it still has no limbs. We are now in a position to trace the development of individual organ systems in detail. Before we do this, however, we must study the development of the placenta.

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6Development of the Placenta

IMPLANTATION

After the ovum is shed from the ovary, it travels through the uterine tube towards the uterus. If fertilization occurs, segmentation of the ovum begins. By the time the fertilized 'ovum' reaches the uterus, it has already become a morula. The morula is still surrounded by the zona pellucida, which prevents it from 'sticking' to the wall of the uterine tube. The cells lining the surface of the morula, constitute the trophoblast. The trophoblast has the property of attaching itself to, and invading, any tissue it comes in contact with. Once the zona pellucida disappears, the cells of the trophoblast stick to the uterine endometrium. This is called implantation (Fig. 6.1). In humans, implantation begins on the 6th day after fertilization. It is aided by proteolytic enzymes produced by the trophoblast. The uterine mucosa also aids the process. The trophoblast of the human blastocyst invades the endometrium of the uterus. The blastocyst goes deeper and deeper into the uterine mucosa till the whole of it comes to lie within the thickness of the endometrium (Fig. 6.2). This is called interstitial implantation (Fig. 6.3A). In some animals (rabbit, cow, dog, monkey), the blastocyst remains in the uterine cavity. This is called central implantation (Fig. 6.313). In others (e.g., rat), the blastocyst comes to lie in a uterine crypt or recess. This is called eccentric implantation (Fig. 6.3C).

DECIDUA

After the implantation of the embryo, the uterine endometrium is called the decidua. When the morula reaches the uterus, the endometrium is in the secretory phase. After implantation, the features of the endometrium, which are seen during the secretory phase of the menstrual cycle, are maintained and intensified. The stromal cells enlarge, become vacuolated, and store glycogen and lipids. This change in the stromal cells is called the decidual reaction.

The portion of the decidua where the placenta is to be formed (i.e., deep to the developing blastocyst) is called the decidua basalis (Fig. 6.4). The part of the decidua that separates the embryo from the uterine lumen is called the decidua capsularis, while the part lining the rest of the uterine cavity is called the decidua parietalis. The decidua basalis

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consists predominantly of large decidual cells which contain large amounts of lipids and glycogen (that presumably provide a source of nutrition for the embryo). 'Me decidua basalis is also referred to as the decidual plate, and is firmly united to the chorion.

At the end of pregnancy, the decidua is shed off, along with the placenta and membranes. It is this shedding off which gives the decidua its name (cf., deciduous trees).

FORMATION OF THE HORIONIC VILLI

The essential functional elements of the placenta are very small finger-like processes or villi. These villi are surrounded by maternal blood. In the substance of the villi, there are capillaries through which the fetal blood circulates. Exchanges between the maternal and fetal circulations take place through the tissues forming the walls of the villi (Fig. 6.5).

The villi are formed as offshoots from the surface of the trophoblast. As the trophoblast, along with the underlying extra-embryonic mesoderm, constitutes the chorion (p. 37) , the villi, arising from it, are called chorionic villi.

The chorionic villi are first formed all over the trophoblast and grow into the surrounding decidua (Fig. 6.6A). Those related to the decidua capsularis are transitory. After some time they degenerate. This part of the chorion becomes smooth and is called the chorion laevae. In contrast, the villi that grow into the decidua basalis undergo considerable development. Along with the tissues of the decidua basalis these villi form a disc shaped mass which is called the placenta (Fig. 6.613). The part of the chorion that helps form the placenta is called the chorion frondosum.

We will now consider how the chorionic villi are formed.

(i) The trophoblast is at first made up of a single layer of cells (Fig. 6.7A). As these cells multiply, two distinct layers are formed (Fig. 6.713). The cells that are nearest to the decidua (i.e., the most superficial cells) lose their cell boundaries. Thus, one continuous sheet of cytoplasm containing many nuclei is formed. Such a tissue is called a syncytium. Hence, this layer of the trophoblast is called the syncytiotrophoblast or plasmodiotrophoblast. Deep to the syncytium, the cells of the trophoblast retain their cell walls and form the second layer called the cytotrophoblast (also called Langhan's layer).

(ii) The syncytiotrophoblast grows rapidly and becomes thick. Small cavities (called lacunae) appear in this layer. Gradually, the lacunae

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increase in size. At first they are irregularly arranged, but gradually they come to lie radially (Figs. 6.8A, 6.9) around the blastocyst. The lacunae are separated from one another by partitions of syncytium, which are called trabeculae. The lacunae gradually communicate with each other, so that eventually one large space is formed. Each trabeculus is now surrounded all round by this lacunar space.

(iii) The syncytiotrophoblast (in which these changes are occurring) grows into the endometrium. As the endometrium is eroded, some of its blood vessels are opened up, and blood from them fills the lacunar space (Fig. 6.10).

(iv) Each trabeculus is, initially, made up entirely of syncytiotrophoblast (Fig. 6.10). Now the cells of the cytotrophoblast begin to multiply and grow into each trabeculus (Fig. 6.11 A). The trabeculus thus comes to have a central core of cytotrophoblast covered by an outer layer of syncytium. It is surrounded by maternal blood filling the lacunar space. The trabeculus is now called a primary villus (Fig. 6.11), and the lacunar space is now called the intervillous space.

(v) The extra-embryonic mesoderm, lining the inner side of the trophoblast, now invades the centre of each primary villus (Fig. 6.12A). The villus thus comes to have a core of mesoderm (Fig. 6.12B). Outside this, there is a layer of cytotrophoblast, which is in turn surrounded by syncytium. This structure is called a secondary• villus.

(vi) Soon thereafter, blood vessels can be seen in the mesoderm forming the core of each villus. With their appearance, the villus is fully formed and is called a tertiary villus (Fig. 6.13). The blood vessels of the villus establish connections with the circulatory system of the embryo. Fetal blood now circulates through the villi, while maternal blood circulates through the intervillous space.

(vii) It will be seen that the cytotrophoblast, that grows into the trabeculus (or villus) does not penetrate the entire thickness of syncytium and, therefore, does not come in contact with the decidua. At a later stage however, the cytotrophoblast emerges through the syncytium of each villus. The cells of the cytotrophoblast now spread out to form a layer that completely cuts oft the syncytium from the decidua. This layer of cells is called the cytotrophoblastic steel (Fig. 6.14). The cells of this shell multiply rapidly, and the placenta increases in sire (viii) The villi that are first formed (as described above) are attached on the fe(a side (Fig. 6.15) to the embryonic mesoderm and on the maternal side to tilt cytotrophoblastic shell. They are, therefore, called anchoring

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villi. Each anchorin) villus consists of a stem (truncus chorii); this divides into a number of branChL. (rami chorii) which in turn divide into finer branches (ramuli chorii). The rarnul are attached to the cytotrophoblastic shell. The anchoring villi give off numerou branches which grow into the intervillous space as free villi (Fig. 6.16). New villi also sprout from the chorionic side of the intervillous space. Ultimately, almost the whole intervillous space becomes filled with villi. As a result, the surface area available for exchanges between and fetal circulations becomes enormous.

These, newly formed, villi at first consist only of syncytiotrophoblast. They are subsequently invaded by cytotrophoblast, mesoderm, and blood vessels, and pass through the stages of primary, secondary and tertiary villi.

FURTHER DEVELOPMENT OF THE PLACENTA

(i) The placenta now becomes subdivided into a number of lobes, by septa that grow into the intervillous space from the maternal side (Fig. 6.17). Each such lobe of the placenta is often called a maternal cotyledon. If the placenta is viewed from the maternal side, the bases of the septa are seen as grooves (Fig. 6.18) while the cotyledons appear as convex areas bounded by the grooves. These lobes generally number 15 to 20. Each lobe contains a number of anchoring villi and their branches. One such villus and its branches constitute a fetal cotyledon. The fully formed placenta has 60 to 100 such fetal cotyledons. The placenta now forms a compact mass and is disc-shaped.

(ii) At full term (9 months after onset of pregnancy) the placenta has a diameter of 6 to 8 inches and weighs about 500 g. After the birth of the child, the placenta is shed off along with the decidua. The maternal surface (formed by the decidual plate) is rough and is subdivided into cotyledons. The fetal surface (chorionic plate) is lined by amnion. It is smooth and is not divided into cotyledons. The umbilical cord is attached to this surface.

Placental Membrane

In the placenta, maternal blood circulates through the intervillous space, and fetal blood circulates through blood vessels in the villi. The maternal and fetal blood do not mix with each other. They are separated by a membrane, made up of the layers of the wall of the villus. These (from the fetal side) are (Fig. 6.13):

(i) the endothelium of fetal blood vessels, and its basement membrane.

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(ii) surrounding mesoderm (connective tissue).

(iii) cytotrophoblast, and its basement membrane.

(vi) syncytiotrophoblast.

These structures constitute the placental membrane or barrier. All interchanges of oxygen, nutrition and waste products take place through this membrane. The total area of this membrane varies from four to fourteen square metres. It is interesting to note that this is equal to the total absorptive area of the adult intestinal tract. As in the gut, the effective absorptive area is greatly increased by the presence of numerous microvilli on the surface of the syncytiotrophoblast.

In the later part of pregnancy, the efficiency of the membrane is increased, by disappearance of the cytotrophoblastic layer from most villi, and by considerable thinning of the connective tissue. This membrane which is at first 0.025 mm thick, is reduced to 0.002 mm. However, towards the end of pregnancy, a fibrinoid deposit appears on the membrane, and this reduces its efficiency.

The tissues, which constitute the placental membrane, differ from species to species, and several types of membranes are recognised (Fig. 6.19). In naming the various types, two-word terms are used. The first word indicates the maternal tissue, and the second word the fetal tissue, that come in contact. In the human placenta, the maternal tissue is blood, and the fetal tissue is chorion. Hence, the human placental membrane is classified as haemo-choreal.

Functions of Placenta

(1) The placenta enables the transport of oxygen, water, electrolytes and nutrition (in the form of carbohydrates, lipids, polypeptides, amino acids and vitamins) from maternal to fetal blood. A full term fetus takes up about 25 ml of oxygen per minute from maternal blood. Even a short interruption of oxygen supply is fatal for the fetus.

(2) It also provides for excretion of carbon dioxide, urea and other waste products produced by the fetus into the maternal blood.

(3) Maternal antibodies (IgG gamma globulins) reaching the fetus through the placenta give the fetus immunity against some infections (e.g., diphtheria and measles).

(4) The placenta acts as a barrier and prevents many bacteria and other harmful substances from reaching the fetus. However, most viruses (including poliomyelitis, measles and rubella) and some

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bacteria can pass across it. Drugs taken by the mother may also enter the fetal circulation and can produce congenital malformations.

As a rule, maternal hormones do not reach the fetus. However, synthetic progestins and synthetic oestrogens (e.g., diethylstilbestrol) easily cross the placenta and can have adverse effects on the fetus (including carcinoma in later life).

(5) While permitting the exchange of several substances between the maternal and fetal blood, it keeps these blood streams separate, thereby, preventing antigenic reactions between them.

(6) The placenta synthesizes several hormones. These are probably produced in the syncytiotrophoblast.

Progesterone secreted by the placenta is essential for maintenance of pregnancy after the fourth month (when the corpus luteum degenerates).

Oestrogens (mainly estriol) produced by the placenta reach maternal blood and promote uterine growth and development of the mammary gland.

Human chorionic gonadotropin (hCG) produced by the placenta is similar in its actions to luteinizing hormone of the hypophysis cerebri. Gonadotropins are excreted through maternal urine where their presence is used as a test to detect a pregnancy in its early stages.

Somatomammotropin (hCS) has an anti-insulin effect on the mother leading to increased plasma levels of glucose and amino acids in the maternal circulation. In this way it increases availability of these materials for the fetus. It also enhances Glucose utilization by the fetus.

Circulation of Blood Through the Placenta

Blood flow through lacunar spaces in the syncytiotrophoblast begins as early as the 9th day of pregnancy. Thereafter, the maternal blood in the intervillus spaces is constantly in circulation. Blood enters the intervillus space through maternal arteries that open into the space. The pressure of blood drives it right up to the chorionic plate. Blood from the intervillus spaces is drained by veins that also open into the same spaces.

In the fully formed placenta, the intervillus spaces contain about 150 ml of blood which is replaced in 15 to 20 seconds (i.e., three to four times per minute).

NORMAL SITE OF IMPLANTATION OF THE OVUM

The uterus can be divided into an upper part, consisting of the

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fundus and the greater part of the body, and a lower part, consisting of the lower part of the body and the cervix. These are called the upper uterine segment, and the lower uterine segment, respectively. It is the upper uterine segment that enlarges during pregnancy. The placenta is normally attached only to the upper uterine segment (Fig. 6.21).

ABNORMAL SITES OF IMPLANTATION OF THE OVUM

Abnormal Implantation within the Uterus

The attachment of the placenta may extend partially, or completely, into the lower uterine segment. This condition is called placenta praevia. It causes difficulty during child-birth and may cause severe bleeding. Various degrees of placenta praevia may be recognised as given below:

(i) First degree: The attachment of the placenta extends into the lower uterine segment, but does not reach the internal os.

(ii) Second degree: The margin of the placenta reaches the internal os, but does not cover it (Fig. 6.22B).

(iii) Third degree: The edge of the placenta covers the internal os, but when the os dilates during child-birth, the placenta no longer occludes it (Fig. 6.22C).

(iv) Fourth degree: The placenta completely covers the internal os, and occludes the os even after it has dilated.

Implantation Outside the Uterus

When the ovum gets implanted at any site outside the uterus, this is called an ectopic preganancy. This may be as follows:

(i) Tubal pregnancy: The blastocyst gets implanted in the uterine tube. Such a pregnancy cannot go on to full term, and may result in rupture of the tube. After rupture, the blastocyst may acquire a secondary implantation in the abdominal cavity (Fig. 6.23), giving rise to an abdominal pregnancy.

(ii) Interstitial tubal implantation: The blastocyst may get implanted in the part of the uterine tube passing through the uterine wall.

(iii) Implantation in the ovary: Fertilization and implantation may occur while the ovum is still in the ovary.

OTHER ANOMALIES OF PLACENTA

Instead of being shaped like a disc, the placenta may be:

(a) bidiscoidal, when it consists of two discs;

(b) lobed, when it is divided into lobes;

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(c) diffuse, when chorionic villi persist all round the blastocyst-. the placenta is thin and does not assume the shape of a disc;

(d) placenta succenturiata, when a small part of the placenta is separated from the rest of it;

(e) fenestrated, when there is a hole in the disc; and

(f) circumvallate, when the peripheral edge of the placenta is covered by a circular fold of decidua.

The umbilical cord is normally attached to the placenta near the centre. However, this attachment may be:

(a) marginal, when the cord is attached at the margin of the placenta ithis type of placenta is called Battledore placenta); or

(b) furcate, when blood vessels divide before reaching the placenta.

(c) When blood vessels are attached to amnion, where they ramify before reaching the placenta, the condition is referred to as velamentous insertion.

MUTUAL RELATIONSHIP OF AMNIOTIC CAVITY, EXTRA-EMBRYONIC COELOM AND UTERINE CAVITY

We have so far considered the fetal membranes (amnion and chorion), and the placenta, mainly in relation to the fetus. Let us now see their relationships to the uterine cavity. These are important, as they help us to understand some aspects of the process of child-birth. The changing relationships will be best understood by first reviewing Figs. 4.6, 4.7 and 4.13 and then by studying Figs. 6.26 to 6.28.

In Fig. 6.26 we see three cavities, namely the uterine cavity, the extra-embryonic coelom, and the amniotic cavity. The outer wall of the extra-embryonic coelom is formed by chorion and the inner wall by amnion. As the amniotic cavity enlarges, the extra-embryonic coelom becomes smaller and smaller. It is eventually obliterated, by fusion of amnion and chorion. The fused chorion and amnion form the amniochorionic membrane. From Fig. 6.27 it will be seen that the wall of the amniotic cavity is now formed by (i) amnion, (ii) chorion, and (iii) decidua capsularis, all three being fused to one another.

Further expansion of the amniotic cavity occurs at the expense of the uterine cavity. Gradually, the decidua capsularis fuses with the decidua parietalis, and the uterine cavity is also obliterated (Fig. 6.28). Still further expansion of the amniotic cavity is achieved by

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enlargement of the uterus. Enlargement of the amniotic cavity is accompanied by an increase in the amount of amniotic fluid.

At the time of parturition (child-birth), the fused amnion and chorion (amniochorionic membrane) (along with the greatly thinned out decidua capsularis), constitute what are called the 'membranes'. As the uterine muscle contracts, increased pressure in the amniotic fluid causes these membranes to bulge into the cervical canal. This bulging helps to dilate this canal. The bulging membranes can be felt through the vagina and are referred to as the 'bag of waters'. Ultimately the membranes rupture. Amniotic fluid flows out into the vagina. After the child is delivered, the placenta and the membranes, along with all parts of the decidua, separate from the wall of the uterus and are expelled from it.

AMNIOTIC FLUID

Amniotic fluid provides support for the delicate tissues of the growing embryo or fetus. It allows free movement and protects the fetus from external injury. It also avoids adhesion of the fetus to amnion. As pregnancy advances the quantity of this fluid increases, till at full term it is about one litre. There is constant exchange of water between the amniotic fluid and maternal blood, the water being completely replaced every three hours. Some time in the fifth month the fetus begins to swallow amniotic fluid. This fluid is absorbed through the gut) into fetal blood and is transferred through the placenta to blood. When the fetal kidneys start working the fetus passes urine into the fluid. This does not cause harm because fetal urine is made up mostly of water i metabolic wastes being removed from blood by the placenta and not through the kidneys).

The condition in which there is too much amniotic fluid (over 1500 ml) is called hydramnios; and when the fluid is too little it is called oligantnios. Both conditions can cause abnormalities in the fetus. They can also cause difficulties during child birth. In some cases hydramnios is associated with atresia of the oesophagus which prevents swallowing of amniotic fluid by the fetus. Oligamios is sometimes associated with renal agenesis as no urine is added to the amniotic fluid.

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7Development of the Human Body Tissues

Many organs of the body are made up of cells that are highly specialized for the performance of certain specific functions (e.g., the nervous system). However, the later part of the body is made up of relatively unspecialized tissues that are widely distributed, and contribute to the formation of many organs. For example, areolar connective tissue is to be found in almost every part of the body. Before we take up a study of the development of particular organs, it will, therefore, be of advantage to consider the mode of formation of these tissues.

EPITHELIA

Every exposed surface in the body—internal or external—is covered by one or more layers of closely packed cells, that are called epithelia. Various types of epithelia are recognized, for details of which see the author's HUMAN HISTOLOGY.

When the three germ layers are formed, they are all arranged in the form of epithelia. After giving origin to the neural tube (and neural crest cells), the remaining cells of the ectoderm by and large persist as the epithelia covering the external surfaces of the body. These include the epithelium of the skin, and of its derivatives like hair, nails and glands; the epithelium of the cornea, and conjunctiva; and the epithelium lining the external acoustic meatus, and the outer surface of the tympanic membrane. After disappearance of the buccopharyngeal membrane, the ectoderm lining the stomatodaeum contributes to the epithelium lining some parts of the mouth. Similarly, after disappearance of the cloacal membrane, the ectoderm of the region forms the lining epithelium of the lower part of the anal canal, the terminal part of the male urethra, and some parts of the female external genitalia. We shall see later that specialized areas of surface ectoderm give rise to the olfactory epithelium, the epithelium of the membranous labyrinth, yrinth, and the anterior epithelium of the lens. The epithelial layers lining the ciliary v body and iris, and the epend ' vina lining the ventricular system of the brain, are derived from the neural tube, and are, therefore, also of ectodermal origin. It can be said that almost all structures through which the individual comes into contact with the environment are of ectodermal origin.

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Like the ectoderm the endoderm also persists, in greater part as a lining epithelium. It forms the epithelium of the whole of the gastrointestinal tract (except the portions of mouth and anal canal lined by ectoderm). A large number of structures are formed as diverticula from the primitive gut. Their lining epithelia are, therefore, endodermal. These are:

(a)the pharyngo-tympanic tube, middle ear, tympanic antrum, and mastoid air cells;

(b)the respiratory tract (larynx, trachea, bronchi, alveoli);

(c)the ducts, and acini, of the pancreas;

(d)the hepatic and bile ducts, and the gall bladder.

The caudal portion of the hindgut (cloaca) contributes to the formation of part of the urinary bladder, the urethra, and possibly the lower part of the vagina. The epithelia of these parts are, therefore, endodermal.

In contrast to the ectoderm, and the endoderm, the mesoderm does not retain its epithelial character in most regions. However, mesodermal cells provide an epithelial lining (usually called mesothelium) for cavities arising within this layer. These include the pericardial, pleural, and peritoneal cavities (from infra-embryonic coelom) and also the cavities of joints, and bursae. The endothelial lining of the heart, blood vessels, and lymphatics, is also of mesodermal origin. Lymph nodes and spleen are also of mesodermal origin.

The mesothelium covering the intermediate mesoderm (on posterior wall of peritoneal cavity), gives rise to the epithelia lining most parts of the urogenital tract. These are:

(a)tubules of kidneys;

(b)ureter;

(c)a small part of urinary bladder (trigone) and of the urethra;

(d)the uterine tubes, uterus, and upper part of vagina;

(e)testes, epididymis, vasa efferentia, ductus deferens, and seminal vesicles.

MESENCHYME

We have seen above that a small 'proportion of mesodermal cells give rise to epithelia. The remaining cells, that make up the bulk of the mesoderm, get converted into a loose tissue called mesenchyme. (Some mesenchymal cells may be derived from the neural crest. According to some authourities these cells are responsible for formation of bones

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and connective tissues of the face, and for some other structures derived from the neural crest). Mesenchymal cells have very little cytoplasm around the nucleus, as most of it is arranged in the form of processes that radiate from the cell and give it a star-shaped appearance (Fig. 7.1). The processes establish contact with those of neighbouring cells to form a network. The spaces of the network are filled by a jelly like intercellular substance.

The mesenchymal cells have the ability to form many different kinds of cells that in turn give rise to various tissues (Fig. 7.2). Thus, chondroblasts arising from mesenchymal cells form cartilage, osteoblasts form bone, myoblasts form muscle, while lymphoblasts and haemocytoblasts form various cells of blood (note that all these cells have the suffix 'blast'). Mesenchymal cells also give rise to endothelial cells from which blood vessels and the primitive heart tubes are formed. However, after differentiation of all these tissues a considerable mass of mesenchymal cells Ls still left and this gives rise to cells of connective tissue.

CONNECTIVE TISSUE

The cells and fibres of connective tissue are derived from mesenchyme. Some mesenchymal cells differentiate into fibroblasts. These have the ability to form zollagen fibres. Reticular fibres are also formed by these fibroblasts. The origin of elastic fibres is, however, not fully understood. Other mesenchymal cells differentiate to form histiocytes, plasma cells, mast cells, fat cells, pigment cells and reticular cells that are seen in connective tissue.

The nature of the connective tissue formed depends upon the density and orientation of the fibres in it. It has been shown that if the developing connective tissue is subjected to stretching, the collagen fibres tend to be laid down along the line of stress. In the subcutaneous tissue, and in the submucosa of most organs, connective tissue remains loose (areolar connective tissue). Loose areolar tissue also fills the interstices that exist in most organs of the body, including glands and muscle, and around blood vessels.

When collagen fibres come to be arranged in sheets, the connective tissue forms structures like deep fascia, intermuscular septa, and aponeuroses of muscles. On the other hand, when collagen is laid down in the form of bundles, ligaments and tendons are formed.

In some situations, elastic fibres predominate (e.g., in ligaments flava) and constitute elastic tissue. Similarly, in some sites the connective tissue is replaced almost entirely by fat cells, forming adipose tissue.

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CARTILAGE

Cartilage is also formed from mesenchyme. At a site where cartilage is to be formed, mesenchymal cells become closely packed. This is called a mesenchymal condensation. The mesenchymal cells then become rounded and get converted into cartilage forming cells or chondroblasts. Under the influence of chondroblasts, the intercellular substance of cartilage is laid down. Some chondroblasts get imprisoned within the substance of this developing cartilage and are called chondrocytes. Some fibres also develop in the intercellular substance. In hyaline cartilage, collagen fibres are present, but are not seen easily. In fibrocartilage, collagen fibres are numerous and very obvious. In some situations, the intercellular substance is permeated by elastic fibres forming elastic cartilage. Mesenchymal cells surrounding the surface of the developing cartilage form a fibrous membrane, the perichondrium.

Hyaline cartilage formed in many parts of the embryo is temporary and is subsequently replaced by bone. In such situations, the cartilage closely resembles the shape of the bone to be subsequently laid down, and is spoken of as a cartilaginous model (Fig. 7.17C).

BONE

Fundamental Structure

Before we consider the formation of bone, it is necessary to review, very briefly, some fundamental facts regarding its structure.

Bone anywhere in the body is composed of units called lamellae. Each lamellus is a thin plate of bone consisting of (1) a groundwork of collagen fibres (often called ossein fibres), (2) a gelatinous matrix, and (3) calcium salts deposited in the matrix. Even the smallest piece of bone is made up of several lamellae. The lamellae are placed one over another (Fig. 7.3B). Small spaces are left between adjoining lamellae. These are called lacunae and contain bone cells or osteocytes . The osteocytes give off numerous small processes that radiate from them. These processes pass through minute canals (canaliculi) that pierce the lamellae and become continuous with processes of neighbouring osteocytes.

In certain situations, lamellae are stacked one over another (as described above) to form plates of bone called trabeculae. These trabeculae form a sponge work, containing numerous cavities. The cavities are filled with a vascular tissue called bone marrow. Nutrition from blood vessels in these spaces diffuses through canaliculi and reaches the osteocytes. This type of bone is called spongy bone.

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In compact bone, on the other hand, the spaces are very small. The lamellae are arranged as concentric plates around a small central canal. Such a collection of lamellae is called a Haversian system or osteone. The canal at the centre of the Haversian system is a Haversian canal. Between the lamellae, there are lacunae (containing osteocytes) and canaliculi just as in trabeculae of spongy bone. It will thus be seen that:

(a)The basic structure of spongy and compact bones is the same as they are both made up of lamellae. They both contain lacunae, and canaliculi, with osteocytes and their processes.

(b)They differ in the relative amount of bony substance and the marrow spaces.

In spongy bone, the marrow spaces occupy a greater area than the bone substance, but in compact bone the marrow spaces are very small being represented only by the Haversian canals.

Osteoblasts and Osteoclasts

In addition to osteocytes, two other types of cells are seen in developing bone. The osteoblasts are bone forming cells. They arise by differentiation of mesenchymal cells. They have the ability to synthesize the intercellular matrix and the fibres that form the organic basis of each lamellus of bone. The deposition of calcium (and other) salts in this matrix also occurs under the influence of osteoblasts. These cells are, therefore, seen wherever bone is being laid down. They have abundant basophilic cytoplasm and are arranged in regular rows, looking very much like an epithelial lining.

The osteoclasts are, on the other hand responsible for bone removal. They are large multinucleated cells and are seen in regions where bone is being absorbed. They are also of mesenchymal origin.

Formation of Bone

From what has been stated above, it is clear that all bone is of mesodermal origin. The process of bone formation is called ossification. In most parts of the embryo, bone formation is preceded by the formation of a cartilaginous model that closely resembles the bone to be formed. This cartilage is subsequently replaced by (not converted into) bone. This kind of bone formation is called endochondral ossification. Bones formed in this way are, therefore, called cartilage bones. In some situations (e.g., the vault of the skull), formation of bone is not preceded by formation of a cartilaginous model. Instead, bone is laid down directly in a fibrous membrane. This is called intramembranous ossification and these bones are called membrane

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holies. These include the bones of the vault of the skull, the mandible and the clavicle.

Intramembranous Ossification

(1) At the site where a membrane bone is to be formed, the mesenchymal cells become closely packed (i.e., a mesenchymal condensation is formed).

(2) The region becomes highly vascular.

(3) Some of the mesenchymal cells lay down bundles of collagen fibres in 111c mesenchymal condensation. In this way a membrane is formed.

(4) Some mesenchymal cells (possibly those that had earlier laid down the collagen fibres) enlarge and acquire a basophilic cytoplasm, and may now be called osteoblasts. They come to lie along the bundles of collagen fibres. These cells secrete a gelatinous matrix in which the fibres get embedded. The fibres may also swell up. Hence the fibres can no longer be seen distinctly. This mass of swollen fibres and matrix is called osteoid.

(5) Under the influence of osteoblasts, calcium salts are deposited in the osteoid. As soon as this happens, the layer of osteoid becomes one lamellus of bone.

(6) Over this lamellus, another layer of osteoid is laid down by osteoblasts. The osteoblasts move away from the lamellus to line the new layer of osteoid. However, some of them get caught between the lamellus and the osteoid (Fig. 7.81)). The osteoid is now ossified to form another lamellus. The cells trapped between the two lamellae become osteocytes.

(7) In this way a number of lamellae are laid down one over another and they together form a trabeculus.

(8) If we now consider the arrangement of collagen bundles in a membrane, we will see that the appearance is somewhat like that in. If we further imagine the process of bone formation, described above, to be occurring along each of these bundles, it will be apparent that bone formed will also follow the same pattern. In this way, typical spongy bone will be formed.

All newly formed bone is spongy. This is converted into compact bone as follows:

(a) The spaces between the trabeculae of spongy bone are filled with tissue that is ascular and has osteogenic cells. The osteogenic cells become osteoblasts and come to line the walls of the spaces. They

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now lay down one lamellus of bone another inside each space. As they do so, the space becomes smaller and caller until it is reduced to a small canal carrying a few blood vessels. This canal s surrounded by rings of concentrically arranged lamellae. Thus Haversian systems (or osteones) are formed, and the spongy bone becomes compact. It must be emphasized, however, that the first formed Haversian systems (prinlar ' N, osteones) are atypical in the composition and arrangement of the bony layers that constitute them. These are soon eroded to form a new series of spaces that are again filled in by bony lamellae that constitute typical Haversian systems (secondan•

osteones). This process of formation and destruction of osteones takes place repeatedly and goes on even after birth. This provides a method for reorientation of osteones to suit the stresses imposed on the bone.

Growth of Bones of Vault of Skull

In the bones of the vault of the skull (e.g., parietal bone), ossification begins in one or more small areas called centres of ossificatiop. Bone is formed as described on p.82.At first it is in the form of narrow trabeculae or spicules. These spicules increase in length by deposition of bone at their ends. As the spicules lengthen, they radiate from the centre of ossification to the periphery. Gradually, the entire mesenchymal condensation is invaded by this spreading process of ossification and the bone assumes its shape. However, even at birth the radiating arrangement of trabeculae is obvious.

The mesenchymal cells lying over the developing bone differentiate to form a membrane called the periosteum. This consists of a superficial fibrous layer and a deeper layer containing cells that can form bone (osteogenic cells which may be considered precursors of osteoblasts).

The embryonic parietal bone, formed as described above, has to undergo considerable growth. After ossification has extended into the entire membrane representing the embryonic parietal bone, this bone is separated from the neighbouring bones by an intervening fibrous tissue that constitutes a suture. Growth in size of the bone can occur by deposition of bone in the region of the sutures (Fig. 7.11). Growth in thickness and size of the bone also occurs when the overlying periosteum forms bone (exactly by the process of intramembranous ossification described (above) over the outer surface of the bone (surface accretion). Simultaneously, there is removal of bone from the inner side. In this way, as the bone grows in size, there is a simultaneous increase in the size of the cranial cavity (Fig. 7.12).

Endochondral Ossification

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The essential steps in the formation of bone by endochondral ossification are as follows:

(a) At the site where the bone is to be formed, the mesenchymal cells become closely packed' to form a mesenchymal condensation.

(b) Some mesenchymal cells become chondroblasts and lay down hyaline cartilage. Mesenchymal cells on the surface of the cartilage form a membrane called the perichondrium. This membrane is vascular and contains osteogenic cells.

(d) The cells of the cartilage are at first small and irregularly arranged. However, in the area where bone formation is to begin, the cells enlarge considerably.

(e) The intercellular substance between the enlarged cartilage cells becomes calcified, under the influence of an enzyme called alkaline phosphatase, which is secreted by the cartilage cells. The nutrition to the cells is thus cut off and they die, leaving behind empty spaces called primary areolae.

(f) Some blood vessels of the perichondrium (which may be called periosteum as soon as bone is formed) now invade the calcified cartilaginous matrix. They are accompanied by osteogenic cells. This mass of vessels and cells is called the periosteal bud. It eats away much of the calcified matrix forming the walls of the primary areolae, and thus creates large cavities called secondary areolae.

(g) The walls of the secondary areolae are formed by thin layers of calcified matrix that have not been dissolved. The osteogenic cells become osteoblasts and arrange themselves along the surfaces of these bars, or plates, of calcified cartilaginous matrix.

(h) These osteoblasts now lay down a layer of ossein fibrils embedded in a gelatinous intercellular substance (i.e., osteoid), exactly as in intramembranous ossification. This osteoid is calcified and a lamellus of bone is formed.

(i) The osteoblasts now lay down another layer of osteoid over the first lamellus. This is also calcified. Thus two lamellae of bone are formed. Some osteoblasts that get caught between the lamellae form osteocytes. As more lamellae are laid down, bony trabeculae are formed.

It may be noted that the process of bone formation in endochondral ossification is exactly the same as in intramembranous ossification. The calcified matrix of cartilage only acts as a support

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for the developing trabeculae and is not itself converted into bone.

(i) At this stage the ossifying cartilage shows a central area (1 in Fig. 7.16A) where bone has been formed. As we move away from this area we see (i) a region where the cartilaginous matrix has been calcified and surrounds dead, and dying, cartilage cells (2 in Fig. 7.16A); (ii) a zone of hypertrophied cartilage cells, in an uncalcified matrix (3); and (iii) normal cartilage (4) in which there is considerable mitotic activity. If we see the same cartilage a little later (Fig. 7.1613), we find that ossification has now extended into zone 2, and simultaneously the matrix in zone 3 has become calcified. The deeper cells of zone 4 have meanwhile hypertrophied, while the more superficial ones have multiplied to form zone 5. In this way, formation of new cartilage keeps pace wit ht the loss due to replacement by bone. The total effect is that the ossifying progressively increases in size.

Development of a Typical Long Bone

We may now consider how a long bone develops.

1. A mesenchymal condensation is seen in the limb-bud in the region where the bone is to be formed.

2. This mesenchymal condensation is converted into a cartilaginous model. This model closely resembles the bone to be formed. It is covered by perichondrium which has a superficial fibrous layer and a deeper layer that has osteogenic cells.

3. Endochondral ossification starts in a small area of the shaft as described above. This area is called the primary centre of ossification.

4. Gradually, bone formation extends from the primary centre towards the ends of the shaft. This is accompanied by enlargement of the cartilaginous model.

5. Soon after the appearance of the primary centre, and onset of endochondral ossification in it, the perichondrium (which may now be called periosteum) becomes active. The osteogenic cells in its deeper layer lay down bone on the surface of the cartilaginous model by intramembranous ossification. This periosteal bone completely surrounds the cartilaginous shaft and, is, therefore, called the periosteal collar. It is first formed only around the region of the primary centre but rapidly extends towards the ends of the cartilaginous model. The periosteal collar acts as a splint, and gives strength to the cartilaginous model, at the site where it is weakened by the formation of secondary areolae. We

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shall see that most of the shaft of the bone is derived from this periosteal collar and is, therefore, intramembranous in origin.

6. At about the time of birth, the developing bone consists of (a) a part called the diaphysis (or shaft), that is bony, and has been formed by extension of the primary centre of ossification, and (b) ends that are cartilaginous. At varying times after birth, secondary centres of endochondral ossification appear in the cartilage forming the ends of the bone. These centres enlarge until the ends become bony. More than one secondary centre of ossification may appear at either end. The portion of bone formed from one secondary centre is called an epiphysis.

For a considerable time after birth, the bone of the diaphysis and the bone of the epiphysis are separated by a plate of cartilage called the epiphyseal cartilage, or epiphyseal plate. This is formed by cartilage into which ossification has not extended either from the diaphysis or from the epiphysis. We shall see that this plate plays a vital role in growth of the bone.

Growth of a Long Bone

A growing bone increases both in length and in thickness.

We have seen that the periosteum lays down a layer of bone around the shaft of the cartilaginous model. This periosteal collar gradually extends to the whole length of the diaphysis. As more layers of bone are laid down over it, the periosteal bone becomes thicker and thicker. However, it is neither necessary nor desirable for it to become too thick. Hence, osteoclasts come to line the internal surface of the shaft and remove bone from this aspect. As bone is laid down outside the shaft it is removed from the inside. The shaft thus grows in diameter, and at the same time, its wall does not become too thick (Fig. 7.20). The osteoclasts also remove the trabeculae lying in the centre of the bone that were formed by endochondral ossification. In this way, a marrow cavity is formed. As the shaft increases in diameter there is a corresponding increase in the size of the marrow cavity. This cavity also extends towards the ends of the diaphysis but does not reach the epiphyseal plate. Gradually, most of the bone formed from the primary centre (i.e., of endochondral origin) is removed, except near the ends, so that the wall of the shaft is made up purely of periosteal bone formed by the process of intramembranous ossification.

To understand how a bone grows in length, we will now have a closer look at the epiphyseal plate. Depending on the arrangement of its cells, three zones can be recognized.

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(a) Zone of resting cartilage: Here, the cells are small and irregularly arranged.

(b) Zone of proliferating cartilage: Here, the cells are larger and are undergoing repeated mitosis. As they multiply, they come to be arranged in parallel columns, separated by bars of intercellular matrix.

(c) Zone of calcification: Here, the cells become still larger and the matrix becomes calcified.

Next to the zone of calcification, there is a zone where cartilage cells are dead and the calcified matrix is being replaced by bone. Growth in length of the bone takes place by continuous transformation of the epiphyseal cartilage to bone (Figs. 7.21, 7.22) in this zone (i.e., on the diaphyseal surface of the epiphyseal cartilage). At the same time, the thickness of the epiphyseal cartilage is maintained by active multiplication of cells in the zone of proliferation. When the bone has attained its hill length, cells in the epiphyseal cartilage stop proliferating. The process of 1'.."i fication, however, continues to extend into it until the whole of the epiphyseal dalc is converted into bone. The bone of the diaphysis and epiphysis then becomes imlinuous. This is called 'fusion of epiphysis'.

Metaphysic

The portion of diaphysis adjoining the epiphyseal plate is called the metaphysic (Fig. 7.23A). It is a region of active bone formation and, for this reason, it is highly vascular. The metaphysis does not have a marrow cavity. Numerous muscles and ligaments are usually attached to the bone in this region. Even after bone growth has ceased, the calcium-turnover function of bone is most active in the metaphysis, which acts as a storehouse of calcium. This region is frequently the site of infection.

Interstitial and Appositional Growth

Tissues grow by two methods. In some of them growth takes place by multiplication of cells (or by increase in intercellular material) throughout the substance of the tissue. This is called interstitial growth. As a result, the tissue expands equally in all directions and its shape is maintained. Cartilage (and most other tissues) grow in this way. To illustrate this, let us suppose that we have a bar of cartilage AD (Fig. 7.24A), subdivided into segments AB, BC and CD. Let us further suppose that this bar of cartilage grows and doubles its length. If we now measure the individual segments (Fig. 7.24B), we will find that each segment has doubled in length.

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On the other hand, bone grows only by deposition of more bone on its surface, or at its ends. This is called appositional growth. To illustrate this, let us suppose we have a bone JM (Fig. 7.24C) subdivided into segments JK, KL and LM. Let us suppose that this bone doubles in length. If we now measure the length of each of these segments, we will find that they are exactly of the same length as before (Fig. 7.24D). The increase in length of the bone is caused wholly by the addition of a new segment MN.

Remodelling

We have seen above that when a tissue grows by interstitial growth it is easy for it to maintain its shape. However, this is not true of bone which can grow only by apposition. This will be clear from Fig. 7.25. In this figure the continuous line represents the shape of a bone end. The dotted line represents the same bone end after it has grown for some time. It will be clear that the shaded areas of the original bone have to disappear if proper shape is to be maintained. This process of removal of unwanted bone is called remodelling. The increase in size of the marrow cavity (p. 93) and the removal of bone from the inner surface of the bones of the vault of the skull (p. 87) are other examples of the same process.

The trabeculae of spongy bone and the Haversian systems of compact bone are s-o arranged that they should be best fitted to bear the stresses imposed on them. This arrangement is not obvious in the bones of a newborn animal and becomes clear only after the bones grow. It is, therefore, apparent that as explained on p. 86 the arrangement of trabeculae and Haversian systems also undergoes change. This process is often called internal remodelling.

Anomalies of Bone Formation

Bone and cartilage formation may sometimes be abnormal as a result of various zenetic and environmental factors. The anomalies may be localised to a particular part of the skeleton, or may be generalised. Anomalies of individual parts of the skeleton are considered in Chapter 10. Some anomalies that effect the skeleton as a whole are as follows:

1. Disorderly and excessive proliferation of cartilage cells in the epiphyseal plate, or the failure of normally formed cartilage to be replaced by bone, leads to the formation of irregular masses of cartilage within the metaphysis. This is called dy,schondroplasia or enchondromatosis.

2. Abnormal masses of bone may be formed in the region of the

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metaphysis and may protrude from the bone. Such a protrusion is called an exostosis, and the condition is called multiple exostoses or diaphyseal aclasis. This condition may be a result of interference with the process of remodelling of bone ends.

3. Calcification of bone may be defective (osteogenesis imperfecta) and may result in multiple fractures.

4. Parts of bone may be replaced by fibrous tissue (fibrous displasia).

5. Bones may show increased density or osteosclerosis. One disease characterised by increased bone density is known as osteopetrosis, or marble bone disease.

6. In the condition called achondroplasia, there is insufficient, or disorderly, formation of bone in the region of the epiphyseal cartilage. This interferes with growth of long bones. The individual does not grow in height and becomes a dwarf. Achondroplasia is inherited as a Mendelian dominant trait. A similar condition in which the limbs are of normal length, but in which the vertebral column remains short, is called chondro-osteo-dystrophy.

7. Anomalous bone formation may be confined to membrane bones. One such condition is cleido-cranial dysostosis in which the clavicle is absent and there are deformities of the skull. On the other hand, anomalies like achondroplasia and exostoses are confined to cartilage bones.

8. Generalised under-development (dwarfism), or over-development, (gigantism) of bone may be present. Sometimes all bones of one half of the body are affected (asymmetric development). Over-development or under-development may be localised, e.g., to a digit, or to a limb.

9. Bone deformities may be secondary to other anomalies, e.g., deformities like amelia (p. 133), ectopia vesicae (p. 271), or anencephaly (p. 325), are associated with anomalies of bones of the region. Muscular weakness, or contractures, may also cause bone deformities.

MUSCLE

Fate of Somites

We have seen that the paraxial mesoderm (p. 45) becomes segmented to form a number of somites, that lie on either side of the developing neural tube. A cross-section through a somite shows that it is a triangular structure and has a cavity (Fig. 7.26A). The somite is

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divisible into three parts.

(a) The ventromedial part is called the sclerotome. The cells of the sclerotome migrate medially. They surround the neural tube and give rise to the vertebral column and ribs.

(b) The lateral part is called the dermatome. The cells of this part also migrate, and come to line the deep surface of the ectoderm covering the body. These cells give rise to the dermis of the skin and to the subcutaneous tissue.

(c) The intermediate part is the myotome. It gives rise to striated muscle as described in the following section.

In the cervical, thoracic, lumbar and sacral regions one spinal nerve innervates each myotome. The number of somites formed in these regions, therefore, corresponds to the number of spinal nerves. In the coccygeal region, the somites exceed the number of spinal nerves but many of them subsequently degenerate.

The first cervical somite is not the most cranial somite to be formed. Cranial to it, there are:

(i) the occipital somites (four to five)-which give rise to muscles of the tongue and are supplied by the hypoglossal nerve (According to some investigations, the cranial occipital somites give origin to laryngeal muscles supplied by the vagus nerve).

(ii) the pre-occipital (or pre-otic) somites, supplied by the third, fourth and sixth cranial nerves. (These somites are not clearly seen in the human embryo. They may be represented by masses of mesenchyme which do not differentiate into dermatome, sclerotome and myotome. To distinguish them from proper somites, they are referred to as somitomeres).

Development of Striated Muscle

We have seen that each myotome establishes contact with one segmental nerve. Hence, theoretically, the embryological derivation of a muscle should be indicated by its nerve supply. On this basis it would be presumed that all the musculature of the body walls and limbs is derived from the myotomes and has subsequently migrated to these regions. Such migration of myotomes can be seen in embryos of some lower animals, but not in the human embryo. In man, the myotomes appear to give origin only to the musculature of the trunk, in whole or in part. The occipital myotomes are believed to give rise to the musculature of the tongue, while the extrinsic muscles of the eyeball are regarded as derivatives of the pre-occipital myotomes.

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Soon after its formation, each myotome, in the neck and trunk, separates into a dorsal part which gives rise to the muscles supplied by the dorsal primary ramus of the spinal nerve, and a ventral part which gives origin to the muscles supplied by the ventral ramus. The myotome may also undergo several-other changes as follows:

1. As stated above, it may migrate to a new site.

2. It may undergo splitting to form several muscles (e.g., various layers of intercostal muscles).

3. The myotome, or its subdivisions, may fuse with other myotomes. In this way, we have the formation of muscles supplied by several spinal nerves.

4. It may degenerate and may form fascial structures.

In addition to the myotomes, striated muscle may also arise in-situ from mesenchyme of the region. The limb muscles develop in this way, in the mesenchyme of the limb buds. The muscles of the anterior parts of the abdominal and thoracic walls probably also arise in-situ.

In the head and neck, striated muscle is also formed from mesenchyme of the branchial arches (Chapter 9). This mesenchyme is probably derived from paraxial mesoderm cranial to the occipital somites (i.e., from the region of the preoccipital somitomeres), with contributions from the neural crest. These muscles are supplied by the nerves of the corresponding arches.

Smooth Muscle

Almost all smooth muscle is formed from mesenchyme. Smooth muscle in the walls of viscera (e.g., the stomach) is formed from splanchnopleuric mesoderm in relation to them. However, the muscles of the iris (sphincter and dilator pupillae) are derived from the ectoderm of the optic cup. The myoepithelial cells of the sweat glands are also of ectodermal origin.

Cardiac Muscle

This is derived from splanchnopleuric mesoderm in relation to the developing heart tubes and pericardium.

Almost all glands, both exocrine and endocrine, develop as diverticula from epithelial surfaces. The gland may be derived by branching of one diverticulum (e.g., parotid) or may be formed from several diverticula (e.g., lacrimal gland, prostate). The opening of the duct (or ducts) is usually situated at the site of the original outgrowth. In the case of endocrine glands (e.g., thyroid, anterior part of hypophysis cerebri) the

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gland loses all contact with the epithelial surface from which it takes origin.

The diverticula are generally solid to begin with and are canalised later (Fig. 7.27C). The proximal parts of the diverticula form the duct system. The distal parts of the diverticula form the secretory elements. Depending on the epithelium from which they take origin, glands may be ectodermal (e.g., sweat glands, mammary glands), endodermal (e.g., pancreas, liver), mesodermal (e.g., adrenal cortex), or of mixed origin (e.g., prostate).

BLOOD

The formation of the cells of blood begins very early in embryonic life (before somites have appeared) and continues throughout life. Blood formation is specially rapid in the embryo to provide for increase in blood volume with the growth of the embryo.

In postnatal life, blood formation takes place in the red bone marrow where all cells of blood are formed. In addition, lymphocytes are also formed in the various lymphoid tissues of the body, i.e., lymph nodes, spleen, thymus, tonsils and Peyer's patches. In prenatal life, blood formation is first seen in relation to the wall of the yolk sac, and in relation to the allantoic diverticulum. With the formation of the liver, in the second month of intrauterine life, this organ becomes an important site of blood formation. Some blood formation also occurs in the spleen. In the third month of intrauterine life, bone marrow begins to be formed and blood formation begins here; with increase in the amount of bone marrow, the blood forming function is almost completely taken over by the marrow by the sixth month.

The precursors of the various types of blood cells are generally regarded as being of mesenchymal origin. However, blood forming cells differentiating in relation to the yolk sac, and in the liver, may be endodermal in origin.

There has been much controversy as to whether the various blood cells are derived from a common ancestral cell (monophyletic theory) or from distinct cell types (polyphyletic theory). Recent evidence favours, their origin from a single cell type. The precursors of the various types of blood cells are indicated.

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8The Skin & its Associated Structures

SKIN

The skin is derived from three diverse components.(a)The epidermis is derived from the surface ectoderm. This is, at

first, single layered. By proliferation it gives rise to typical stratified squamous epithelium. Many of the superficial layers are shed off. These get mixed up with secretions of sebaceous glands to form a whitish sticky substance (vernix caseosa) which covers the skin of the newborn infant (Fig. 8.213). The vernix caseosa has a protective function.

(b)The melanoblasts (or dendritic cells) of the epidermis are derived from the neural crest (p. 299).

(c) The dermis is formed by condensation and differentiation of mesenchyme underlying the surface ectoderm. This mesenchyme is believed to be derived from the dermatome of the somites (p. 98).

The line of junction between dermis and epidermis is at first straight (Fig. 8.3A). Subsequently, the epidermis shows regularly spaced thickenings that project into the dermis. The portions of dermis intervening between these projections form the dermal papillae (Figs. 8.3B, Q. Still later, surface elevations (epidermal ridges) are formed by further thickening of the epidermis in the same situation.NAILSThe nails develop from the surface ectoderm. The ectoderm at the tip of each digit becomes thickened to forma primary nail field. Subsequently this thickening migrates from the tip of the digit onto its dorsal aspect.The cells in the most proximal part of the nail field proliferate to form the root of the nail. Here the cells of the germinal layer multiply to form a thick layer of cells called the germinal matrix. As the cells in this matrix multiply, they are transformed into the nail substance which corresponds to the stratum lucidum of the skin (Fig 8.4).The migration of the primary nail fields from the tips of the digits to their dorsal aspect explains why the skin of the dorsal aspect of the terminal part of the digits is supplied by nerves of the ventral aspect.HAIR

The hair are also derived from surface ectoderm. At the site where a hair-follicle is to form, the germinal layer of the epidermis proliferates to form a cylindrical mass, that grows down into the dermis

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(Figs. 8.5A, B). The lower end of this downgrowth becomes expanded and is invaginated by a condensation of mesoderm, which forms the papilla (Figs. 8.5C, D). The hair itself is formed by proliferation of germinal cells overlying the papilla. As the hair grows to the surface, the cells forming the wall of the downgrowth surround it and form the epithelial root sheath. An additional sheath is formed by the surrounding mesenchymal cells. A typical hair follicle is thus formed (Fig. 8.5E).

SWEAT GLANDS

A sweat gland develops as a downgrowth from the epidermis (Fig. 8.6A). The jowngrowth is at first solid but is later canalised. The lower end of the downgrowth ---comes coiled (Fig. 8.6B), and forms the secretory part of the gland.

ANOMALIES OF SKIN AND ITS APPENDAGES

Albinism: Absence of pigment in skin, hair and eyes. Absence of pigment may patchy.

1. Aplasia: The skin may fail to develop in certain regions.

2. Asplasia: The skin may be abnormal in structure. Numerous varieties of dysplasia are described. There may be congenital growths of the skin.

3. Dysplasia may be part of maldevelopment of various ectodermal derivatives including hair, teeth, sweat glands and sebaceous glands.

4. Hair may be absent over the scalp (congenital alopecia). The eyebrows and eyelashes may also be absent. Absence of hair in any part of the body is called atrichia, while overgrowth of hair is called hypertrichosis.

5. Anonychia: Nails may be absent. Occasionally they may show overdevelopment.

MAMMARY GLANDS

In some animals (e.g., bitches) a series of mammary glands are present on either side of the midline, on the ventral surface of the trunk. These are situated along a line that extends from the axilla to the inguinal region. In the human embryo, the ectoderm becomes thickened along this line to form mammary ridges or lines (Fig. 8.7). Most of this line soon disappears. Each mammary gland develops from a part of this line that overlies the pectoral region.

In the region where the mammary gland is to form, a thickened mass of epidermal cells is seen projecting into the dermis. From this

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thickened mass, sixteen to twenty solid outgrowths arise, and grow into the surrounding dermis. The thickened mass of epidermis, as well as these outgrowths, are now canalised. The secretory elements of the gland are formed by proliferation of the terminal parts of the outgrowths. The proximal end of each outgrowth forms one lactiferous duct. The ducts at first open into a pit formed by cavitation of the original epithelial thickening. However, the growth of underlying mesoderm progressively pushes the wall of this pit outwards, until it becomes elevated above the surface and forms the nipple. The mammary gland remains rudimentary in the male. In females, the ducts and secretory elements undergo extensive development during puberty and pregnancy.

Developmental Anomalies of the Mammary Glands

(i) Amastia: The gland may be absent on one or both sides.

(ii) Athelia: The nipple may be absent.

(iii) Polythelia and polymastia: Supernumerary nipples may be present anywhere

(iv) Inverted or crater nipple: The nipple may fail to form resulting in lactiferous ducts opening into a pit. This causes difficulty in suckling.

(v) The gland may be abnormally small (micromastia) or abnormally large (macromastia).

(vi) Gynaecomastia: The male breast may enlarge as in the normal female and may even secrete milk.

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9

The Pharyngeal Arches & their Derivatives

The formation of the foregut has been considered in Chapter 5. Reference to will show that after the establishment of the head fold, the foregut is bounded ventrally by the pericardium, and dorsally by the developing brain. Cranially, it is at first separated from the stomatodaeum by the buccopharyngeal membrane. When this membrane breaks down, the foregut opens to the exterior through the stomatodaeum.

At this stage, the head is represented by the bulging caused by the developing brain. While the pericardium may be considered as occupying the retion of the future thorax. The two are separated by the stomatodaeum which is the future mouth. It is, thus, apparent that a neck is not yet present.

The neck is formed by the elongation of the region between the stomatodaeum and the pericardium. This is achieved, partly, by a ‘descent’ of the developing heart. However, this elongation is due mainly to the appearance of a series of mesodermal thickenings in the wall of the cranial-most part of the foregut. These are called the pharyngeal, or brqanchial, arches.

A coronal section through the foregut (the part destined to form the pharynx), before the appearance of the pharyngeal arches. At this stage, the endodermal wall of the foregut is separated from the surface ectoderm by a layer of mesoderm. Soon, thereafter, the mesoderm comes to be arranged in the form of six bars that run dorso-ventrally in the side wall of the foregut. Each of these ‘bars’ growns ventrally in the floor of the developming pharynx and fuses with the corresponding ‘bar’ of the opposite side to from a pharyngeal or branchial arch. In the interval between any two adjoining arches, the endoderm extends outwards in the form of a pouch (endodermal or pharyngeal pouch) to meet the ectoderm which dips into this interval as an ectoderma cleft.

The first arch is also called the mandibular arch; and the second, the hyoid arch. The third, fourth and sixth arches do not have special names. The fifth arch disappears soon after its formation, so that only five arches remain.

The following structures are formed in the mesoderm of each arch.

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1. A skeletal element: This is cartilaginous to begin with. It may remain cartilaginous may develop into bone, or may disappear.

2. Striated muscle: This is supplied by the nerve of the arch. In later development, this musculature may, or may not, retain its attachment to the skeletal elements derived from the arch. It may subdivide to form a number of distinct muscles, which may migrate away from the pharyngeal region. When they do so, however, they carry their nerve with them and their embryological origin can thus be determined from their nerve supply.

3. An arterial arch: Ventral to the foregut, an artery called the ventral aorta develops. Dorsal to the foregut, another artery called the dorsal aorta, is formed. A series of arterial arches connect the ventral and dorsal aorate. One such arterial arch lies in each pharyngeal arch. In a subsequent development, the arrangement of these arteries become greatly modified. The fate of the arterial arches is considered in Chapter 15.

Each pharyngeal arch is supplied by a nerve. In addition to supplying the skeletal muscle of the arch, it supplies sensory branches to the overlying ectoderm, and endoderm (Fig. 9.2). In some lower animals, each arch is supplied by two nerves Fig. 9.3). The nerve of the arch itself runs along the cranial side of the arch. This is called the post-trematic nerve of the arch (trema = trench). Each arch also receives a branch from the nerve of the succeeding arch. This runs along the caudal border of the arch, and is called the pre-trematic nerve of the of the arch. In the human embryo, however, a double innervation is to be seen only in the first pharyngeal arch.

DERIVATIVES OF THE SKELETAL ELEMENTS

1. The cartilage of the first arch is called Meckel's cartilage. The incus and malleus (of the middle ear) are derived from its dorsal end. The ventral part of the cartilage is surrounded by the developing mandible, and is absorbed. The part of the cartilage extending from the region of the middle ear to the mandible disappears, but its sheath (perichondrium) forms the anterior ligament of the malleus and the sphenomandibular ligament.

Mesenchyme of the first arch is also responsible for formation of bones of the face including the maxilla, the mandible, the zygomatic bone, the palatine bone and part of the temporal bone. Also see first arch syndrome.

2. The cartilage of the second arch forms the following:

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(a) Stapes

(b) Styloid process

(c) Stylohyoid ligament (from sheath)

(d) Smaller (lesser) cornu of hyoid.

(e) Superior part of body of hyoid.

(Note that all structures listed start with 'S').

(3) The following structures are formed from the cartilage of the third

arch:

(a)Greater cornu of hyoid bone.

(b)Lower part of the body of hyoid bone.

(4) The cartilages of the larynx are derived from the fourth and sixth arches with a possible contribution from the fifth arch, but their exact derivation is controversial.

NERVES AND MUSCLES OF THE ARCHES

All the muscles derived from a pharyngeal arch are supplied by the nerve of the arch and can, therefore, be indentified by their nerve supply. The nerves of the arches and the muscles supplied by them are given in the following table:Arch Nerve of arch Muscles of archFirst Mandibular Tensor tympani, tensor palati, medial and

lateral pterygoids, masseter, temporalis, mylohyoid, anterior belly of digastric.

Second Facial Stapedius, stylohyoid, posterior belly of digastric, muscles of face, auricular muscles, occipito-frontalis, platysma.

Third Glossopharyngeal Stylopharyngeus.Fourth Superior laryngeal Muscles of pharynx,Sixth Recurrent laryngeal Soft palate and larynx.

We have already seen that these nerves not only supply muscles, but also innervate the parts of skin and mucous membrane derived from the arches. Some of the nerves (e.g., glossopharyngeal) have only a small motor component and are predominantly sensory. As stated above, the first arch has a double nerve supply. The mandibular nerve is the post-trematic nerve of the first arch, while the chorda -Impani (branch of facial nerve) is the pre-trematic nerve. This double innervation reflected in the nerve supply of the anterior two-thirds of the tongue which are -rived from the ventral part of the first arch (see p.

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158).

Some recent investigations suggest that mesenchyme giving rise to muscles of pharyngeal arches is derived from paraxial mesoderm cranial to the occipital somites (i.e., from the region of the preoccipital somites); and that its organization influenced by neural crest cells. Although paraxial mesoderm here does not -orm typical somites, it shows partial segmentation into seven masses of mesenchyme zalled somitomeres. The structures derived from the seven somitomeres and from five occipital somites that follow them, have been described as follows:

Sornitonieres I and 2: Muscles supplied by oculomotor nerve.

Somitomere 3: Superior oblique muscle supplied by trochlear nerve. Somitomere 4: Muscles of first pharyngeal arch (supplied by mandibular nerve). Somitomere 5: Lateral rectos muscle supplied by abducent nerve.

Somitomere 6: Muscles of second pharyngeal arch (supplied by facial nerve). Somitomere 7: Stylopharyngeus (third arch) supplied by glossopharyngeal nerve. Occipital somites 1 and 2: Laryngeal muscles (fourth to sixth arches) supplied by the vagus nerve.

Occipital somites 2 to 5: Muscles of tongue supplied by hypoglossal nerve.

If we accept this view of the origin of branchial musculature, there would be no significant reason to distinguish between it and muscle derived from somites.

FATE OF ECTODERMAL CLEFTS

After the formation of the pharyngeal arches, the region of the neck is marked on the outside by a series of grooves, or ectodermal clefts. The dorsal part of the first cleft (between the first and second arches) develops into the epithelial lining of the external acoustic meatus. The pinna (or auricle) is formed from a series of swellings or hillocks, that arise on the first and second arches, where they adjoin the first cleft. The ventral part of this cleft is obliterated.

The second arch grows much faster than the succeeding arches and comes to overhang them (Fig. 9.5). The space between the overhanging second arch and the third, fourth and sixth arches is called the cervical sinus. Subsequently, the lower overhanging border of the second arch fuses with tissues caudal to the arches. The side of the neck (which was thus far marked by the ectodermal clefts) now becomes smooth. The cavity of the cervical sinus is normally obliterated. Part of it may persist and give rise to swellings that lie in the neck, along

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the anterior border of the sternocleidomastoid. These are called branchial cysts, and are most commonly located just below the angle of the jaw. If such a cyst opens onto the surface, it becomes a branchial sinus. Rarely, a cervical sinus may open into the lumen of the pharynx in the region of the tonsil.

FATE OF ENDODERMAL POUCHES

The endodermal pouches take part in the formation of several important organs Fig. 9.6). These are listed below.

first Pouch

(a)Its ventral part is obliterated by formation of the tongue (see p. 156).

(b)Its dorsal part receives a contribution from the dorsal part of the second N-uch, and these two together form a diverticulum that grows towards the region ,f the developing ear. This diverticulum is called the tubo-tympanic recess. The ,roximal part of this recess gives rise to the auditory (pharyngotympanic) tube, and the distal part of the middle ear cavity, including the tympanic antrum.

Second Pouch

(a) The epithelium of the ventral part of this pouch contributes to the formation of the tonsil (see p.160).

b) The dorsal part takes part in the formation of the tubo-tympanic recess.

Third Pouch

This gives rise to the inferior parathyroid glands, and the thymus.

Fourth Pouch

This gives origin to the superior parathyroid glands, and may contribute to the thyroid gland.

Fifth or Ultimobranchial Pouch

A fifth pouch is seen for a brief period during development. In some species it gives rise to the ultimobranchial body. Its fate in man is controversial. It is generally believed to be incorporated into the fourth pouch, the two together forming the caudal pharyngeal complex. The superior parathyroid glands arise from this complex. The complex probably also gives origin to the parafollicular cells of the thyroid gland.

DEVELOPMENT OF THE THYMUS

The thymus develops from the endoderm of the third pharyngeal

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pouch (which also gives rise to the inferior parathyroid glands). Early in development, this pouch is cut off, both from the pharyngeal wall and from the surface ectoderm.

After separation from the inferior parathyroid rudiment, each thymic rudiment has a thinner cranial part and a broader caudal part. The thinner portion forms the cervical part of the thymus. The broader parts, of the two sides, enter the thorax and become united to each other by connective tissue.

The endodermal cells of the thymus are invaded by vascular mesoderm which contains numerous lymphoblasts. This invading mesenchyme partially breaks up the thymic tissue into isolated masses, and thus gives the organ its lobulated appearance.

Fragmentation of the cervical part of the thymus may give rise to accessory thymic tissue. Such tissue, present in relation to the superior parathyroid glands, is believed to arise from the fourth pouch.

The thymus is relatively large at birth. It continues to increase in weight till puberty. Thereafter, it gradually undergoes atrophy.

DEVELOPMENT OF PARATHYROID GLANDS

Parathyroid glands are derived from:

(i) endoderm of the third pharyngeal pouch (parathyroid III), and

(i) endoderm of the fourth pharyngeal pouch (parathyroid IV).

As the third pouch also gives origin to the thymus, this organ is closely related to parathyroid III. When the thymus descends towards the thorax, parathyroid III is carried caudally along with it for some distance. Meanwhile, parathyroid IV is prevented from descending caudally, because of the close relationship of the fourth pouch to the developing thyroid gland. As a result, parathyroid III becomes caudal to parathyroid IV. Hence, the parathyroid glands derived from the fourth pouch become the superior parathyroid glands and those derived from the third pouch become the inferior parathyroid glands (Fig. 9.7).

In keeping with their developmental history, the superior parathyroid glands are relatively constant in position, but the inferior parathyroid glands may descend into the lower part of the neck or even into the anterior mediastinum. Alternatively, they may remain at their site of origin and are then seen near the bifurcation of the common carotid artery.

DEVELOPMENT OF THE THYROID GLAND

After the formation of the pharyngeal arches, the floor of the pharynx has the appearance shown in Fig. 9.8. The medial ends of the

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two mandibular arches are separated by a midline swelling called the tuberculum impar. Immediately behind the tuberculum, the epithelium of the floor of the pharynx shows a thickening in the middle line (Fig. 9.9A). This region is soon depressed below the surface to form a diverticulum called the thyroglossal duct (Fig. 9.913). The site of origin of the diverticulum is now seen as a depression called the foramen caecum. The diverticulum grows down in the midline into the neck. Its tip soon bifurcates (Fig. 9.9Q. Proliferation of the cells of this bifid end gives rise to the two lobes of the thyroid gland.

The developing thyroid comes into intimate relationship with the caudal pharyngeal complex (see p. 118) and fuses with it (Fig. 9.91)). Cells arising from this complex are believed to give origin to the parafollicular cells of the thyroid which may represent the ultimobranchial body of lower animals.

ANOMALIES OF THE THYROID GLAND

A. Anomalies of Shape

(i) The pyramidal lobe is present so often that it is regarded as a normal structure. It may arise from the isthmus (Fig. 9.10A) or from one of the lobes (Fig.9. 1013, Q. It may have no connection with the rest of the thyroid, and may be divided into two or more parts (Fig. 9.101)). In extent, it may vary from a short stump (Fig. 9.10A) to a process reaching the hyoid bone (Fig. 9.10C).

(i)The isthmus may be, absent (Fig. 9.11A).

(i) One of the lobes of the gland may be very small (Fig. 9.1113), or absent (Fig. 9.11 ).

B. Anomalies of Position (Fig. 9.12)

(i) Lingual thyroid: The thyroid may lie under the mucosa of the dorsum of the tongue and may form a swelling that may cause difficulty in swallowing.

(i)Intro-lingual thyroid: The thyroid may be embedded in the muscular substance of the tongue.

(i) Suprahyoid thyroid: The gland may lie in the midline of the neck, above the hyoid bone.

(ii)Infrahyoid thyroid: The gland may lie below the hyoid bone, but above its normal position.

(ii) Intrathoracic thyroid: The entire gland, or part of it, may lie in the

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thorax.

Note that when thyroid tissue is present in the anomalous positions described above, an additional thyroid may or may not be present at the normal site.

C. Ectopic Thyroid Tissue

Small masses of thyroid tissue have been observed in the larynx, trachea, oesophagus, pons, pleura, pericardium and ovaries. Masses of ectopic thyroid tissue have been described in relation to the deep cervical lymph nodes (lateral aberrant thyroids) but these are now believed to represent metastases in the lymph nodes from a carcinoma of the thyroid gland.

D. Remnants of the Thyroglossal Duct

These remnants may persist and lead to the formation of:

(a) Thyroglossal cysts, that may occur anywhere along the course of the duct. They may acquire secondary openings on the surface of the neck to form fistulae.

(b) Thyroglossal fistula opening at the foramen caecum.

(c) Carcinoma of the thyroglossal duct.

In the surgical removal of thyroglossal cysts and fistulae, it is important to remove all remnants of the thyroglossal duct. In this connection, it has to be rememberekt that the duct is intimately related to the hyoid bone (Fig. 9.12).

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10

Development of the Human Skeleton

The process of bone formation has been considered in Chapter 7. We have seen that all bone is of mesodermal origin, and that bones can be classified as cartilage bones or membrane bones, on the basis of their mode of ossification. We shall now consider the development of some individual parts of the skeleton.

THE VERTEBRAL COLUMN

The vertebral column is formed from the sclerotomes of the somites (p. 98). The cells of each sclerotome get converted into loose mesenchyme. This rn spnchyme migrates medially and surrounds the notochord (Fig. 10.1). The mesenchyme then extends backwards on either side of the neural tube and surrounds it (Fig. 10.2). Extensions of this mesenchyme also take place laterally in the position to be subsequently occupied by the transverse processes, and ventrally in the body wall. in the position to be occupied by the ribs.

For some time the mesenchyme derived from each somite can be seen as a distinct segment (Fig. 10.3A). The mesenchymal cells of each segment are at first uniformly distributed. However, the cells soon become condensed in a region that runs transversely across the middle of the segment. This condensed region is called the perichordal disc. Above and below it there are less condensed parts (Fig. 10.313). The mesenchymal basis of the body, (or centrum) of each vertebra is formed by fusion of the adjoining, less condensed parts of two segments (Fig. 10.313). The perichordal disc becomes the intervertebral disc. The neural arch, the transverse processes and the costal elements are formed in the same way as the body. The interspinous and intertransverse ligaments are formed in the same manner as the intervertebral disc. The notochord disappears in the region of the vertebral bodies. In the region of the intervertebral discs, the notochord becomes expanded and forms the nucleus pulposus (Fig. 10.30).

From the above account we may note that:

1. The vertebra is an intersegmental structure made up from portions of two somites. The position of the centre of the somite is represented by the intervertebral disc.

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2. The transverse processes and ribs are also intersegmental. They separate the muscles derived from two adjoining myotomes.

3. Spinal nerves are segmental structures. They, therefore, emerge from between the two adjacent vertebrae and lie between the two adjacent ribs.

4. The blood vessels supplying structures derived from the myotome (e.g., intercostal vessels) are intersegmental like the vertebrae. Therefore, the intercostal and lumbar arteries lie opposite the vertebral bodies.

The mesenchymal basis of the vertebra is converted into cartilage by the appearance of several centres of chondrification. Three primary centres of ossification appear for each vertebra; one for each neural arch and one for the greater part of the body (centrum). At birth the centrum and the two halves of the neural arch are joined by cartilage (Fig. 10.4A). Note that the posterolateral parts of the body are formed from the neural arch. The lines of junction between the parts derived from the centrum and neural arches form the neurocentral joints.

Congenital Anomalies of Vertebral Column

1. One or more vertebrae may be absent, the caudal vertebrae being more commonly affected. Absence of the coccyx alone, or of the sacrum and coccyx, may be seen. In rare cases, all vertebrae caudal to the tenth thoracic have been found to be absent. There may be only four lumbar vertebrae.

2. Additional vertebrae may be present. There may be thirteen thoracic vertebrae. The sacrum may show six segments.

3. Part of a vertebra may be missing. Various anomalies result, depending on the part that is absent.

(i) The two halves of the neural arch may fail to fuse in the midline. This condition is called spina bifida. The gap between the neural arches may not be obvious (spina bifida occulta), or may be large enough for meninges and neural elements to bulge out of it (see meningocoele and meningomyelocoele, (p. 326). The defect may be unilateral, part of one lamina being deficient; in this case the spine is attached to the normal lamina. If the defect is bilateral, the spine is absent.

Spina bifida in a fetus can be recognized by ultrasound examination. Examination of amniotic fluid shows increased levels of alpha feto proteins (AFP) in a case with spina bifida.

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(ii)The vertebral body may ossify from two primary centres which soon fuse. One of these parts may fail to develop, resulting in only half of the body being present. This is called hemivertebra. It is usually associated with absence of the corresponding rib.

(iii) The two halves of the vertebral body may be formed normally but may fail to fuse. The vertebral body then consists of two hemivertebrae. Sometimes the gap between the two halves is large enough for meninges and nerves to bulge forward between them (anterior spina bifida).

(iv) A vertebra may be represented by a shapeless mass of bone.

(4) Two or more vertebrae that are normally separate may be fused to each other. Such fusion may occur in the cervical region (Klippel-Feil syndrome). The atlas vertebra may be fused to the occipital bone (occipitilization of atlas). The fifth lumbar vertebra may be partially or completely fused to the sacrum (sacralisation of 5th lumbar vertebra). Fusion of adjacent vertebrae may affect only part of the vertebra, e.g., spines may be fused.

(5) Parts of the vertebral column that are normally fused to each other may be separate. The first sacral vertebra may be separate from the rest of the sacrum (lumbarisation of the first sacral vertebra). The odontoid process may be separate from the rest of the axis vertebra.

(6) The articular facets may be abnormal in orientation, or may be deficient. When this happens in the lower lumbar region, the body of the fifth lumbar vertebra may slip forwards over the sacrum. This is called spondylolisthesis. vlolisthesis. Rarely, the fourth lumbar vertebra may slip forwards over the fifth vertebra.

(7) The vertebral canal may be divided into two lateral halves by a projecting shelf of bone, which splits the spinal cord longitudinally into two halves (diastematomylia).

(8) Ossification of the vertebral bodies may be defective thus reducing the total length of the spine. This can lead to the formation of dwarfs who have a short trunk but have limbs of normal length (chondro-osteo-dystrophy, ystrophy, see p. 98).

(9) A peculiar tumour arising from cells of the primitive knot may be seen attached to the lower end of the spine. Various tissues may be seen in it. Such a growth is called a sacrococcygeal teratoma.

Anomalies of the vertebrae are of practical importance in that:

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(i) They may cause deformities of the spine. The spine may be bent on itself' (congenital scoliosis). Deformities of cervical vertebrae may lead to tilting of the head to one side and its rotation to the opposite side (Congenital torticolis). This deformity may be secondary to a contracture of the sternocleidomastoid muscle.

(i) The spinal nerves, or even the spinal cord, may be implicated. They may be subjected to abnormal pressure leading to paralysis.

(ii)They are frequently the cause of backache.

THE RIBS

The ribs are derived from ventral extensions of the sclerotomic mesenchyme that forms the vertebral arches. These extensions are present not only in the thoracic region but also in the cervical, lumbar and sacral regions. They lie ventral to the mesenchymal basis of the transverse processes with which they are continuous.

In the thoracic region, the entire extension (called the primitive costal arch) undergoes chondrification, and subsequent ossification, to form the ribs. However, some mesenchyme between it and the developing transverse process does not undergo chondrification; it becomes loose and forms the costotransverse joint. In the cervical, lumbar and sacral regions, chondrification and ossification of the costal arch is confined to the region in immediate relationship to the transverse process. The bone formed from the arch is fused to the transverse process and is referred to as the costal element of the process. The contributions made by the costal element to the cervical, lumbar and sacral vertebrae are shown in Fig. 10.5.

THE STERNUM

The sternum is formed by fusion of two sternal bars, or plates, that develop on zither side of the midline. According to some workers, the sternal bars are formed independently but soon fuse with the ventral ends of the developing ribs. Other workers believe that the bars are formed by fusion of the ventral ends of the ribs with one another.

The fusion of the sternal bars first occurs at the cranial end (manubrium) and proceeds caudally (Figs. 10.6B, C). The manubrium and the body of the sternun are chondrified, and ossified, separately. The xiphoid process ossifies only late in life.

Anomalies of the Sternum and Ribs

(1) Some ribs that are normally present may be missing. Unilateral absence of a rib is often associated with hemivertebra.

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(2) The first, or the twelfth, rib may be underdeveloped.

(3) Accessory ribs may be present. Such a rib may be attached to the seventh cervical vertebra (cervical rib), or to the first lumbar vertebra (lumbar rib).

(4) The anterior end of a rib may be bifid.

(5) Ribs may show abnormal fusion to one another.

(6) In the condition of ectopia Gordis, the anterior thoracic wall is deficient and parts of the sternum and ribs may be missing.

(7) When the fusion of two sternal bars is faulty, the body of the sternum shows a partial or even a complete midline cleft. Minor degrees of non-fusion may result in a bifid xiphoid process or in midline foramina. Transverse clefts may also occur.

(8) The manubrium may be abnormally long, with the result that the third rib may articulate at the sternal angle.

(9) The eighth costal cartilage may articulate directly with the sternum (i.e., it may be a true rib).

(1) In the condition called funnel chest, the lower part of the sternum and the attached ribs are drawn inwards into the thorax. The primary defect is that the central tendon of the diaphragm is abnormally short.

(2) The upper part of the sternum (and related costal cartilages) may project forwards (pigeon breast).

THE SKULL

The skull is developed from mesenchyme surrounding the developing brain. This mesenchyme comes into close relationship with the following structures which also contribute to the development of the skull:

(a) Cranial to the first cervical somite there are four occipital somites. The first occipital somite disappears. The remaining three give rise to sclerotomes. The mesenchyme arising from these sclerotomes does not retain its segmentation but merges to form one mass that helps to form part of the base of the skull in the region of the occipital bone. The notochord is closely related to these somites and is. thus, present in relation to the base of the developing skull. It extends as far forward as the hypophysis cerebri. Remnants of the notochord in this situation sometimes give rise to tumours related to the posterior wall of the pharynx.

(b) The developing internal ear (otic vesicle), and the region of the

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developing nose, are surrounded by mesenchymal condensations called the otic, and nasal, capsules respectively. These capsules also take part in forming the mesenchymal basis of the skull.

(c) The first branchial arch is closely related to the developing skull. It soon shows two subdivisions, called the mandibular and maxillary processes. Some bones of the skull are formed in the mesoderm of these processes.

The mesenchyme shows condensations in regions where the skull bones are to develop. A number of chondrification centres arise in the region of the base of the skull (including the otic and nasal capsules). The cartilages formed do not correspond to individual bones of the adult skull but follow a complicated pattern. The base of the skull is formed by ossification in relation to these cartilages.

The mesenchyme destined to form the sides and vault of the skull, and also the facial skeleton, is not chondrified but is converted into bone by intramembranous ossification. It thus follows that some bones of the skull are formed in membrane, some in cartilage, and some partly in membrane and partly in cartilage, as listed below.

(a) Bones that are Completely Formed in Membrane

(i) The frontal and parietal bones are formed in relation to mesenchyme covering the developing brain.

(i) The maxilla (excluding the premaxilla), zygomatic and palatine bones, and part of the temporal bones, are formed by intramembranous ossification of the mesenchyme of the maxillary process.

(i) The nasal, lacrimal and vomer bones are ossified in the membrane covering the nasal capsule.

(b) Bones that are Completely Formed in Cartilage

The ethmoid bone and the inferior nasal concha are derived from the cartilage of the nasal capsule. The septal and alar cartilages of the nose represent parts of the capsule that do not undergo ossification.

(c) Bones that are Partly Formed in Cartilage and Partly in Membrane

(i) Occipital: The interparietal part is formed in membrane; the rest of the bone is formed by endochondral ossification.

(ii) Sphenoid: The lateral part of the greater wing, and the pterygoid laminae, are formed in membrane; the rest is cartilage bone.

(iii)Temporal: The squamous and tympanic parts are formed in

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membrane. The petrous and mastoid parts are formed by ossification of the cartilage of the otic capsule. The styloid process is derived from the cartilage of the second branchial arch.

(iv)Mandible: Most of the bone is formed in membrane in the mesenchyme of the mandibular process. The ventral part of Meckel's cartilage gets embedded in the bone. The condylar and coronoid processes are ossified from secondary cartilages that appear in these situations.

The development of the hyoid bone has been described in Chapter 9.

Mesenchyme giving rise to bones of the face, the hyoid bone, and parts of the temporal and frontal bones is said to be derived from (or organized under the influence of) the cranial part of the neural crest.

Anomalies of the Skull

(1) The greater part of the vault of the skull is missing in cases of anencephaly (p. 325).

(2) The skull may show various types of deformity. In one syndrome, deformities of the skull are associated with absence of the clavicle (cleidocranial dysostosis p. 98). Premature union of the sagittal suture gives rise to a boat-shped skull (scaphocephaly). Early union of the coronal suture results in a pointed skull (acrocephaly). Asymmetrical union of sutures results in a twisted skull (plagiocephaly). When the brain fails to grow the skull remains small (microcephaly). v).

(3) The bones of the vault of the skull may be widely separated by expansion of the cranial cavity in congenital hydrocephalus.

(4) In a rare congenital condition called Hand-Schuller-Christian disease, large defects are seen in the skull bones. The primary defect is in the reticuloendothelial system; the changes in the bones are secondary.

(1) The occipital bone may be fused to the atlas vertebra.

(2) See mandibulo-jacial dysostosis (p. 143).

FORMATION OF THE LIMBS

The bones of the limbs, including the bones of the shoulder and pelvic girdles, are formed from mesenchyme of the limb buds. With the exception of the clavicle (which is a membrane bone), they are all formed by endochondral ossification.

The limb buds are, paddle-shaped, outgrowths that arise from the side-wall, of the embryo at the beginning of the second month of

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intrauterine life (Fig. 10-7). Each bud is a mass of mesenchyme covered by ectoderm. At the tip of each limb bud, the ectoderm is thickened to form the apical ectodermal ridge. This ridge has an inducing effect on underlying mesenchyme causing it to remain undifferentiated and to proliferate. Areas away from the ridge undergo differentiation into cartilage, muscle, etc.

The forelimb buds appear a little earlier than the hindlimb buds. As each forelimb bud grows, it becomes subdivided by constrictions into arm, forearm and hand. The hand itself soon shows outlines of the digits, which then separate from each other (Fig. 10.8). Similar changes occur in the hindlimb.

The limb buds are at first directed forward and laterally from the body of the embryo (Fig. 10.9). Each bud has a preaxiall (or cranial) iborder and a postaxial border (Fig. 10.10). The thumb and great toe are formed on the preaxial border. The radius is the preaxial bone of the forearm. In a later development, the forelimb is adducted to the side of the body (Fig. 10.10). The original ventral surface forms the anterior surface of the arm, forearm and hand. In the case of the lower limb, the tibia is the preaxial bone of the leg. Adduction of this imb is accompanied by medial rotation with the result that the great toe and tibia come to lie on the medial side. The original ventral surface of the limb is represented by the inguinal region, the medial side of the lower part of the thigh, the popliteal surface of the knee, the back of the leg and the sole of the foot.

The forelimb bud is derived from the part of the body wall belonging to segments C4, C5, C6, C7, C8, TI and T2. It is, therefore, innervated by the corresponding spinal nerves. The hindlimb bud is formed opposite the segments L2, L3, L4, L5, S I and S2.

Joints

The tissues of joints are derived from mesenchyme intervening between developing bone ends. This mesenchyme may differentiate into fibrous tissue, forming a fibrous joint (syndesniosis), or into cartilage forming a cartilaginous joint. In the case of some cartilaginous joints (synchondrosis or primary cartilaginous joints), the cartilage connecting the bones is later ossified, with the result that the two bones become continuous. This is seen, typically, at the joints between the diaphyses and epiphyses of long bones.

At the site where a s ynovialjoint is to be formed, the mesenchyme is usually seen in three layers. The two outer layers are continuous with the perichondrium covering the cartilaginous ends of the articulating

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bones. The middle layer becomes loose and a cavity is formed in it. The cavity comes to be lined by a mesothelium that forms the synovial membrane. The capsule, and other ligaments, are derived from the surrounding mesenchyme.

Anomalies of Limbs

1. One or more limbs of the body may be partially, or completely, absent (phocomelia, amelia). In meromelia the limb is represented only by a hand or foot which it attached to the trunk by a small irregular bone. These conditions may be produced by harmful drugs, and is seen characteristically in the children of mothers who have been given the drug thalidomide during pregnancy (see p. 363). Absence of limb bones, in whole or in part, may also occur independently and may be the cause of deformities of the limb.

2. There may be a congenital constriction across part of a limb. If the constriction is deep enough it may lead to a congenital amputation.

3. Congenital contractures may limit the range of movement of the limb.

4. Part of a limb may be deformed. Deformities are most frequently seen in the 7evion of the ankle and foot, and are of various types. In the most common variety -,f deformity, the foot shows marked plantar flexion (equines: like the horse), and Inversion (varus). Hence this condition is called talipes equinovarus, or club foot. The condition may be unilateral or bilateral. A similar condition may, rarely, be seen in the hand (club hand). The medial longitudinal arch of the foot may be poorly developed (pes planes or flat foot). The angle between the neck and shaft of the femur may be less than normal (coxa vera).

5. There may be abnormal fusion (bony or fibrous) between different bones of the limb. Adjoining digits may be fused (vndactyly). The phalanges of a digit may be fused to one another (synphalangia). The radius or ulna may be fused to the humerus. The tarsal bones may be fused to one another.

6. A digit may be abnormally large (macrodactyly), or abnormally short brachydactyly). In arachnodactyly, the fingers are long and thin (spider fingers).

7. Supernumerary digits may be present (polydactyly). A digit (most commonly the thumb) may have an extra phalanx.

8. The palm or sole may show a deep longitudinal cleft. In a deformity known as lobster claw, there is a cleft between the

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second and fourth digits (the third digit being missing). The medial two digits may be fused. The, lateral two digits may also be fused.

9. The limbs may remain short in achondroplasia (see p. 98).

10. Sometimes the bone ends forming a joint are imperfectly formed (congenital dysplasia). As a result, they do not fit each other properly, or may even be completely separate (congenital dislocation). The hip joint is most commonly affected. Rarely the knee, shoulder, elbow or wrist may be affected.

11. The scapula may be situated higher than normal (Sprengel's shoulder).

12. One or more muscles of the limb (e.g., pectoralis major) may be absent.

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